Nutritional requirements for detoxication of environmental chemicals.

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Nutritional requirements for detoxication of environmental chemicals Dennis V. Parke

a

a

School of Biological Sciences , University of Surrey , Guildford, Surrey, GU2 5XH, UK Published online: 10 Jan 2009.

To cite this article: Dennis V. Parke (1991) Nutritional requirements for detoxication of environmental chemicals, Food Additives & Contaminants, 8:3, 381-396, DOI: 10.1080/02652039109373987 To link to this article: http://dx.doi.org/10.1080/02652039109373987

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FOOD ADDITIVES AND CONTAMINANTS, 1991, VOL. 8, NO. 3, 3 8 1 - 3 9 6

Nutritional requirements for detoxication of environmental chemicals DENNIS V. PARKE School of Biological Sciences, University of Surrey, Guildford, Surrey, GU2 5XH, UK

Downloaded by [New York University] at 09:38 21 July 2015

(Received 3 October 1990, revised 16 January 1991; accepted 29 January 1991) The biological defence systems against oxygen radical toxicity and chemical toxicity, and their component enzymes, are described, and the nutritional requirements for biological defence against chemical and oxygen toxicity, including calories; protein, lipids and lipotropes, vitamins and minerals, are reviewed in the context of their contribution to the mechanisms of detoxication. Modulation of the cytochromes P-450, and hence toxicity, by dietary components are considered; the P450I family, induced by food pyrolysis mutagens, and the P450IIE family, induced by alcohol and fasting, contribute substantially to chemical toxicity and carcinogenicity. It is concluded that: (i) the detoxication system of terrestrial fauna has evolved over > 300 million years to protect animals from dietary plant toxins; (ii) protection against chemical and oxygen toxicity requires all categories of nutrients; and (iii) the role of food and nutrition in detoxication is essential to survival. Keywords: detoxication, chemical toxicity, cytochromes P-450, nutrients, glutathione, oxygen radicals

Introduction

For the past few decades it has been fashionable to write disparagingly about our diet and to condemn food, especially food additives and contaminants, for many of the ills that afflict man, whereas in reality our food has never been more safe, and we have come to realize that food is essential in insuring a high degree of protection against chemical and oxygen toxicity (Avery-Jones 1989). A number of eminent medical authorities have written to correct these misconceptions of food safety (Avery-Jones 1989) and, similarly, this review has been written to publicize the vitally important role of food in maintaining the efficacy of the biological defence systems. There has long been an awareness that good nutrition affords protection against chemical toxicity and the toxicity of ionizing radiation, and conversely that malnutrition greatly impairs the body's natural resistance to cellular damage from toxic chemicals and reactive oxygen radicals (Parke and Ioannides 1981). Some of the first documented evidence for this protective effect of food was recorded by American surgeons in the 1914-18 war, when wounded soldiers exposed to starvation and dehydration for several days had a poor change of surviving surgery. Studies revealed that the high rate of post-surgical mortality was associated with liver damage, probably attributed to the hepatotoxic effects of the anaesthesia (Bourne 1936, Babcock 1944). It was postulated that malnutrition deprived the casualties of the protective effects of liver glutathione, which led to the studies of Stekol (1937) and others on the importance of glutathione and sulphur amino acids 0265-203X/91 $3.00 © 1991 Taylor & Francis Ltd.

D. V. Parke


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in protecting experimental animals from the toxic effects of chemicals, in particular, bromobenzene. Much later, Pessayre et al. (1979) drew attention to the marked difference in the hepatotoxic effects of bromobenzene in rats that had been fed normally and those that had been starved for 24 h (see figure 1). More recently, it has been shown that fasting induces a specific hepatic cytochrome P-450 (P450 IIE1) which has a propensity for the generation of oxygen radicals by futile cycling, and can result in lipid peroxidation and hepatotoxicity (Ekstrom and IngelmanSundberg 1989). Similar adverse effects of malnutrition on chemical toxicity have been noted by epidemiologists, and it is widely considered that cancer of the gastrointestinal tract in west Africa is more frequent in the poorly nourished, and those exposed to kwashiorkor and/or marasmus in earlier life. Similarly, in a recent epidemic of spastic paraparesis in Mozambique, the syndrome was associated with prolonged droughts and malnutrition (Ministry of Health, Mozambique, 1984a,b). Normally, the staple diet of cassava is prepared by maturing for several months and boiling in abundant water to hydrolyse the cyanoglycosides and remove the toxic cyanide before eating; moreover, the carbohydrate-rich cassava is supplemented with fish protein obtained from coastal areas by trading surplus cassava. Prior to the outbreak of spastic paraparesis, there had been a long-standing drought, and the only variety of cassava to grow was one high in cyanogenic glycosides; even that was in short supply and was eaten without maturing to remove the cyanide. Water was insufficient for the normal safe method of preparation and cooking, and there was insufficient cassava for trading for fish. The consequence was chronic cyanide poisoning, depletion of cobalamin and sulphur amino acids used in thiocyanate detoxication, exacerbated by the shortage of dietary sulphur amino acids due to the lack of fish. The neurotoxic symptoms were probably attributed to all of these and also to the shortage of sulphate (PAPS) required to detoxicate the neurotoxic chemicals present in local plants that were being eaten to supplement the meagre diet.

a

o o

Dose of bromobenzene (mg/Wg)

Figure 1. Effect of 24 h fasting on the hepatotoxicity of bromobenzene to rats. (Reproduced from Pessayre et al. 1979).


Nutrition and the detoxication of chemicals

383

In toxicity testing, the nutrition of experimental animals can be critical, and changes in nutrition have been known to reverse findings in the rodent carcinogenesis assay. In one case, the riboflavin content of the experimental animal diet was found to markedly affect the tumorigenicity of an azo compound under investigation, due to the catalytic effect of the flavin on the microbial reduction of the azo compound in the rodent gastrointestinal tract. With some azo compounds, the compound itself, if planar, may be tumorigenic, and is detoxicated by azo reduction; in contrast, other azo compounds, that are non-planar and noncarcinogenic may, on azo reduction, give rise to one or more aromatic amines which undergo activation by ./V-hydroxylation to form mutagens and carcinogens. In the treatment of cancer, and rheumatoid disease, the widely used cytotoxic drug, methotrexate, acts by depriving malignant and normal cells of folate; the malignant cells, which exhibit poor intercellular co-operativity, undergo deprivation and necrosis, with consequent regression of the tumour, or the excessive proliferation of leucocytes of chronic inflammation is arrested. However, there is evidence that such treatment may cause fatalities, and 'rescue' therapy involving nutritional supplementation with dietary folate has been used to prevent this. Biological defence systems against toxicity

Oxygen toxicity It is now appreciated that the toxic consequences of exposure to ionizing radiation result mostly, if not entirely, from cellular damage caused by reactive oxygen species, such as hydroxyl radicals and singlet oxygen. Ionizing radiation, or any other kind of radiation, imparts energy to the biological system, resulting in the homolytic scission of water molecules and the formation of toxic oxygen radicals. Oxygen radicals also arise from (i) electron leakage in the mitochondrial cytochrome chain (Sohal et al. 1990), (ii) futile cycling of the cytochromes P-450 (see figure 2) (Ekstrom and Ingelman-Sundberg 1989), (iii) redox cycling of xenobiotic quinones (Powis et al. 1981), (iv) transoxygenation associated with the

Ah receptor

->•

Protein kinase c cascade

P450I Reactive intermediates

DNA

Malignancy

neoantigens I Immunotoxicity

P450 n B

futile cycling

P450 n E

futile cycling

P450IV

peroxisomal proliferation

-*•

Oxygen radicals

species dependent dose dependent sex dependent

Figure 2. The roles of the cytochromes P-450 in the activation of drugs and chemicals, and in the production of oxygen radicals.


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D. V. Parke

conversion of PGG2 to PGH2 and HPETE to HETE in prostaglandin synthesis (Eling and Krauss 1985), and (v) from leucocyte cytotoxic activity (Biemond et al. 1986). These reactive oxygen species result in the oxygenation and peroxidation of polyunsaturated fatty acids, especially those of the phospholipids in the endoplasmic reticulum and other cellular membranes, giving rise to lipid peroxidation, loss of normal cell function, and tissue necrosis. Reactive oxygen species also result in oxidative scission of NAD and NADP nucleotides, oxidize intracellular glutathione and sulphydryl enzymes, damaged DNA and activate the protein kinase c cascade with consequent DNA replication and tissue proliferation, all of which can result in tissue necrosis, mutations, malignancy, and death of the organism. The biological defence system against oxygen radical toxicity is an elaborate, integrated array of enzymes, antioxidants and radical scavengers, dependent largely on glutathione (GSH) and involving glutathione reductase (GSSG reductase), glutathione S-transferase, glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase, the tocopherols, ascorbic acid, carotenoids, ubiquinone and bilirubin. The superoxide dismutases, alone and in concert with catalase, play a major role in protecting the biological organism against oxidant stress (Deby and Goutier 1990). SOD also suppresses radical chain oxidation of GSH, and SOD in conjunction with GSH constitutes an important integral component of the cellular antioxidant defence system (Munday and Winterbourn 1989). In addition to GSH peroxidase (GPX) and the several other enzyme components of the antioxidant defence system, a further enzyme, namely, phospholipid hydroperoxide glutathione peroxidase (PHGPX), a lipophilic selenoprotein, which can directly reduce membrane lipid peroxides including cholesterol hydroperoxides, has recently been identified (Nagaska et al. 1989, .Thomas et al. 1990). In addition to the antioxidant roles of the dietary vitamins, ascorbic acid (hydrophilic) and tocopherols (lipophilic, vitamin E), the carotenoid pigments, which are widely distributed in fruit and vegetables, play an important role in protecting biological systems against the harmful effects of reactive species of oxygen, by quenching excited molecules such as singlet oxygen, and also by acting as antioxidants (Krinsky 1989). Chemical toxicity The biological defence system to protect the mammalian organism against the adverse effects of toxic chemicals, involves oxidative metabolism (phase 1) and conjugation (phase 2), catalysed by the mixed-function oxidases and conjugases of liver, kidney, gastrointestinal tract, and other tissues, which generally effect the detoxication of the chemicals concerned. Recent studies of the molecular biology of these enzymes, especially the cytochromes P-450, have indicated that they evolved during a rapid evolutionary burst following the emergence of terrestrial animal species some 300 million years ago; the consumption of terrestrial flora for food resulted in the development of protective toxic chemicals in plants, and the subsequent evolution of detoxication mechanisms in animals, in a reciprocating process known as co-evolution. However, the metabolism of toxic chemicals does not always result in detoxication, and for the past decade or so it has been realized that the same metabolic processes of oxidative metabolism which usually result in detoxication may result also in activation with the formation of reactive intermediates, leading to mutations, malignancy, cytotoxicity and immunotoxicity.


385


The ultimate defence against these reactive intermediates, formed from toxic chemicals, is once again glutathione, which is also the ultimate defence against oxygen toxicity and ionizing radiation. The toxicity of chemicals, oxygen, and reactive intermediates are therefore closely interlinked, as may be seen from figure 2. Oxygen toxicity is more fundamental than chemical toxicity, as the biological defence system against oxygen radicals developed much earlier in the primitive cell, at the time of the first appearance of dioxygen on this planet, whereas the defence system against toxic chemicals in mammalia developed mostly during the evolution of terrestrial fauna. Nutritional requirements for biological defence against toxicity The primary requirement of both biological defence systems is for energy, which is needed to effect the reduction of NADP to NADPH, required for: (i) reductive regeneration of glutathione (GSH) from oxidized glutathione (GSSG) and (ii) activation of the cytochrome P-450 microsomal mixed-function oxidase system (see figure 3). Protein, especially that rich in sulphur amino acids, is required for the synthesis of glutathione, and also for the synthesis of the cytochromes P-450 and other enzymes involved in detoxication. Lipotropes are required for the synthesis of phospholipids which are essential components of the endoplasmic reticulum and other biological membranes, and are vital for activity of the cytochromes P-450 and for certain conjugation reactions (see figure 4). Also essential are numerous vitamins including nicotinamide for NADP synthesis, riboflavin for FAD, vitamin A and retinoids for radical scavenging, tocopherols as antioxidants, and of course, essential minerals, including iron for synthesis of the haemoproteins, and selenium for formation of the protective enzyme glutathione peroxidase. Energy Energy is required for the generation of NADPH, by the direct oxidative pathway or from isocitrate dehydrogenase, to provide the reducting equivalents for activation of the cytochromes P-450 and mixed-function oxidation of xenobiotics, and to provide glutathione reductase with reducing equivalents to maintain the intracellular level of reduced GSH, which is needed as coenzyme for glutathione PROTEIN

CARBOHYDRATE

LIPIDS

lipotropes GSH reductase GSH

•*

• NADPH

Phospholipids

UDPGA PAPS

N Detoxication GSH of reactive conjugations oxygen radicals

Sulpho conjugations

Glucuronide conjugations

Cytochrome P450 oxygenations

Figure 3. The roles of proteins, carbohydrates and lipids in the detoxication of toxic chemicals and oxygen radicals. GSH = glutathione; PAPS = 3'-phosphoadenosine 5'-phosphosulphate; UDPGA = uridine diphosphoglucuronic acid; NADPH = reduced nicotinamide adenine dinucleotide phosphate.

386

D. V. Parke

COOH

CH2

folaie, B12 .

c(

CH2NH2 pyridoxal

Glycine

methionine. folate, B

12-

CH2OH

CH 2 OH

CH2OH

Serine

Ethanolamine

Choline

phosphaddic acid

Phosphatidykthanolamine


Uncoupling of cytochromes P450 from reductase

O2'~radicals

Protein, folate iron

™eihionine> Phosphatidylcholine

Cytochromes P450 + P450 reductase

P450 oxygenations FAD, FMN Ribofiavin

Figure 4. The importance of lipotropes and phosphatidylcholine in microsomal cytochrome P-450 oxygenations.

peroxidase and the glutathione S-transferases to detoxicate oxygen radicals, lipid peroxides and toxic chemicals respectively (see figure 3). Many hepatotoxic chemicals, e.g. carbon tetrachloride and carbon disulphide, exert their toxic effects by damaging cellular membranes, including those of the mitochondria and endoplasmic reticulum, by carbon and oxygen radical production and consequent lipid peroxidation, thereby interfering with cellular energy production. These hepatotoxic effects impair liver ATP formation, polyamine synthesis and hepatic cellular regeneration. Fructose 1,6-diphosphate, a readily available source of ATP which can cross the cellular membrane barrier, increases liver ATP levels, polyamine synthesis, and hepatic regeneration, and decreases liver injury following administration of the hepatotoxic, lethal mixture of chlordecone plus carbon tetrachloride (Rao and Mehendale 1989). Nutrition, especially proteinenergy nutrition, also affects the activities of individual cytochromes P-450, a deficiency in calories enhancing the activities of P450 IIE1 and probably P450 IV (Hong et al. 1987), while protein-energy malnourished rats show regioselective changes in the hydroxylation of endogenous substrates, such as testosterone (Gil et al. 1988) and arachidonate, which affects the relative extents of formation of the various eicosanoids (Orellana et al. 1989). Oral adminstration of glucose for 48 h to rats inhibited the in vitro microsomal metabolism of benzo(a)pyrene, the formation of mutagenic products and DNA adduct formation, possibly by effecting changes in microsomal lipids (Vance et al. 1990); in contrast, oral fructose for several weeks increased by 100% the incidence of AT-nitrosomorpholine-induced hepatocellular carcinoma which was associated with a similar increase in glucose 6-phosphate dehydrogenase (Enzmann et al. 1989), and hence possibly, microsomal mixed-function oxygenation.

387



Protein and sulphur amino acids The activity of the mixed-function oxidases increases with increased dietary protein up to a protein content of 35% (Kato et al. 1980), and rats fed a diet deficient in sulphur amino acids had decreased P-450 activity but increased UDPGA transferase activity (Magdalou et al. 1979). Sulphur amino acids are required for the synthesis of GSH and PAPS and P-450 and hence may both enhance and diminish the toxicity of drugs and chemicals. Methionine deficiency decreased liver GSH and increased the hepatotoxicity of paracetamol in mice (Meydani and Hathcock 1984) and rats (Price and Jollow 1989). In general, higher cytochrome P-450 activity means increased detoxication and hence, higher intakes of dietary protein result in higher mixed-function oxidase activities, greater detoxication and lower toxicity, as may be seen from the acute oral toxicities of a number of pesticides in rats on high and low protein diets (Boyd and Taylor 1969) (table 1). Dietary protein, and particularly the methionine intake, are also important for the effective utilization of Se and hence for GSH peroxidase activity and the detoxication of lipid peroxides (Sunde et al. 1981). High protein diets enhance the oxidative drug-metabolizing activity in humans, accelerating the metabolism of antipyrine, theophylline, propranolol, oestradiol, etc., and a change of parenteral nutrition from glucose to amino-acids (23% branched-chain) increased the clearance of aminopyrine in healthy volunteers by 20% (Pantuck et al. 1989); conversely, vegetarians on a low protein diet have a decreased clearance of antipyrine (Mucklow et al. 1979). Specific dietary amino acids also have specific inductive effects on the mixed-function oxidase system, and tryptophan has been claimed to be unique among amino acids in that it increases hepatic protein synthesis, cytochrome P-450 content and various cytochrome P-450-mediated oxygenase activities (Everts and Mostafa 1981), although more recently i.p. injection of DL-methionine to rats has been shown similarly to induce cytochromes P-450 and bs, P-450 reductase, UDPGA-transferase and aminopyrine demethylase activity (Kamat et al. 1989).

Table 1. Acute oral toxicities for several pesticides administered to rats on low and high protein diets.a LD50 on Pesticide Chlordane Lindane Malathion DDT

Endosulfan Carbaryl Parathion Captan

Normal protein diet Low protein diet (mg/kg; body wt) 135 ± 30 95 ±35 600 ± 140 165 ± 35 24 ± 10 89 ± 11 4-9± 1-3 480 ± 110

265 ± 45 185 ± 16 1400 ± 100 480 ± 15 100 ±16 575 ± 51 37 ± 5 12600 ± 2 100

Ratio of LD50 values on normal/low protein diets 2-0 2-0 2-3 2-9 4-2 6-5 7-6 26

"Albino rats were fed 28 days from weaning on the low protein diet (3-5% casein) or on the normal protein diet (26%). Data from Boyd and Taylor (1969).


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D. V. Parke

Lipids and lipotropes Dietary lipids, in excess, are generally considered to increase the toxic effects of chemicals, especially if saturated, and to enhance the toxic effects of ionizing radiation if polyunsaturated, due to an acceleration of lipid peroxide formation. However, Newberne, in several experimental animal studies (see table 2), has shown the need for dietary lipotropes, which are required for the synthesis of phospholipids and biological membranes, essential for microsomal metabolism and the detoxication of xenobiotic chemicals and carcinogens; these lipotropes include choline, methionine, glycine, folate, vitamin B12, pyridoxal, polyunsaturated fatty acids, and phosphate (see figure 4). Phosphatidylcholine is an essential component of the microsomal mixed-function oxidase system, and the reconstituted solubilized component enzymes, the cytochromes P-450 and NADPH-P450 reductase, require phosphatidylcholine for full enzymic activity (Lu etal. 1974). A choline-deficient diet, in the absence of any added carcinogen or toxic chemicals, results in lipid peroxidation and autoxidative liver damage in rats within days, and induces liver cell cancer in > 50% of the animals within 2 years; these oxygen radical-mediated effects of choline deficiency were prevented by simultaneous adminstration of N-4methylphenylacetyl-dehydroalanine, a scavenger of superoxy anion and hydroxyl radical, but not by BHA (butylated hydroxyanisole) and other antioxidants (Ghoshal et al. 1990). Dietary deficiencies in the lipotropes, choline and methionine increase the tumorigenic effects of diethylnitrosamine in rat liver by strong promoting effects (Sawada etal. 1990), and similarly enhance the carcinogenicity of nitrosamines, aflatoxin, ethionine and 2-acetamidofluorene (Newberne and McConnell 1990). Both quality and quantity of the mixed-function oxidase system are affected by dietary fat (Wade and Norred 1976), and although polyunsaturated fats are needed for phospholipid and membrane biosynthesis, increased content of polyunsaturated lipid in the endoplasmic reticulum increases the susceptibility of the membrane to lipid peroxidation, exposing cytochrome P-450 to radical attack and consequent deactivation (Tien etal. 1981). High fat diets have been shown to promote the incidence of mammary, colonic and pancreatic carcinogenesis in animal models and recently a high fat diet has been shown to enhance the pulmonary tumorigenic effect of 4-nitroquinoline 1-oxide in mice (Imaida et al. 1989). Dietary fibre also plays a role, at least in colon carcinogenesis, and dietary fat and fibre have been shown to Table 2. Effect of high fat diet" on chemical tumorigenesis in rats. Tumour incidence (%) Carcinogen Aflatoxin BNi (375 ng) JV-Nitrosodiethylamine (40 ppm, 12 weeks) 2-Acetamidofluorene (0-02%, 18 weeks) 1,2-Dimethylhydrazine (150 mg/kg)

Normal diet

High fat diet

11 24

87 60

19

41

56

85

"The high fat diet is slightly deficient in lipotropes (choline). From Rogers and Newberne (1975).


389


affect iV-methyl-N'-N-nitro-nitrosoguanidine (MNNG, a direct-acting carcinogen)induced colon cancer in rats in a complex, interactive manner; fat had little effect when dietary fibre was high but enhanced tumour incidence when fibre was low (Sinkeldam etal. 1990). Vitamins Studies to demonstrate the beneficial effects of various vitamins on the biological defence against toxic agents, have emphasized the protective effects of vitamin C, vitamin A and retinoids. Ascorbate is required for cholesterol homeostasis and bile acid synthesis, as it is essential for the regulatory, cytochrome P-450-mediated 7a-hydroxylation of cholesterol (Ginter 1989). Similary, this vitamin is essential in detoxication as it is required for the cytochrome P-450 oxygenation of xenobiotics and, in the case of toxic chemicals, decreases the covalent binding of reactive intermediates, reduces toxic quinones, eliminates free radical metabolites, and blocks the formation of nitrosamines (Ginter 1989); ascorbate rather than glutathione protects against the toxicity of paracetamol by reducing the paracetamol phenoxyl radical (Ramakrishna Rao etal. 1990). Ascorbic acid deficiency decreases microsomal mixed-function activity and the activity of UDPGA transferase, the latter being quantitatively the most important detoxifying enzyme in mammalia; these changes are associated with an increase in membrane fluidity of the endoplasmic reticulum (Neumann and Zannoni 1990). However, in subjects with iron overload, such as the healthy Bantu, blood and tissue ascorbate is abnormally low, and feeding them ascorbic acid has produced lipid peroxidation by reduction of the iron and hydroxyl radical formation, often with deleterious consequences, sometimes fatal (Halliwell and Gutteridge 1989). Dietary vitamin A and retinoids were shown to have a protective effect against chemical carcinogens (table 3) (Newberne and McConnell 1980); deficiency increased the binding of benzo(a)pyrene metabolites to hamster tracheal epithelial

Table 3. Effect of vitamin A on experimental benzo(a)pyrene lung cancer in hamsters. Malignant tumours of respiratory tract Diet

Number

%

Low vitamin A (0-3% pg/g retinyl aceetate) High vitamin A (30 ^g/g retinyl acetate) Control vitamin A (2 /tg/g retinyl acetate) plus 13 c/s-retinoic acid during BP dosage plus 13 ciy-retinoic acid after BP dosage plus 13 cis-retinoic acid before and after BP dosage

102/127

80

40/88

46

46/89

52

38/83

46

11/84

13

4/91

4

Data from Newberne and McConnell (1980).


390

D. V. Parke

DNA (Genta et al. 1974), although lower benzo(a)pyrene hydroxylase activity was found in lung tissue of vitamin A-deficient rabbits (Miranda et al. 1979). Retinoic acid inhibits the proliferation of carcinogen-induced, hormone-dependent human breast carcinoma cells (Fontana et al. 1990), and retinol was shown to decrease the mutagenicity of cooked-food mutagens, the aminoimidoazaarenes, IQ, MelQ, and MelQx, by inhibiting their cytochrome P450I-dependent metabolic activation (Ioannides et al. 1990). /?-Carotene, canthaxanthin and other carotenoids of orange juice, tomato paste and carrots inhibited the mutagenesis of aflatoxin Bi, independent of any conversion to retinol (He and Campbell, 1990). Nevertheless, ingestion of excessive amounts of vitamin A can be deleterious, and may be associated with birth defects; tissues with excessively high levels of vitamin A, such as the livers of polar bear and Arctic fox have long been known to be toxic, often fatally so. Riboflavin is an essential component (FAD and FMN) of NADPH-cytochrome P-450 reductase, and P-450-mediated hydroxylase activity is decreased in riboflavin deficiency (Yang 1974). FAD is the electron acceptor from NADPH while FMN is the electron donor to P-450; in riboflavin deficiency FAD is in excess and FMN is in deficit resulting in an abnormal P-450 reductase (Vermilion et al. 1981, Hara and Taniguchi 1982) that might facilitate electron leakage and oxygen radical formation. Riboflavin also stimulates nitro and azo reductase activities, and azo dye-induced cancer has been shown to be related to the riboflavin content of the diet and liver (Williams et al. 1970). Thiamine deficiency, in contrast to deficiencies of vitamin C, riboflavin and folic acid, increases cytochrome P-450, cytochrome bs and P-450 reductase, and hence increases the metabolism of aminopyrine, ethylmorphine, benzo(a)pyrene, aniline and numerous other xenobiotics. A recent study showed that thiamine deficiency specifically induces cytochrome P450IIE1, the cytochrome that generates oxygen radicals and is concerned in the metabolism of alcohol, paracetamol, carbon tetrachloride and benzene; thus providing an insight into the mechanism of the potentiation of chemical-induced hepatotoxicity associated with thiamine deficiency (Yoo et al. 1990). The tocophenols are well-known biological antioxidants and all isomers are able to quench the reactivity of singlet oxygen (Kaiser et al 1990). The ability of vitamin E to scavenge free radicals and inhibit lipid peroxidation probably plays an important role in protecting the microsomal cytochrome P-450 system and in enhancing drug metabolism (Meydani 1987). Vitamin B12 (hydroxycobalamin) has a unique role in detoxication in that it detoxicates cyanide to form cyanocobalamin which is excreted in the urine; furthermore, methylcobalamin enhances the synthesis of phosphatidylcholine, which is essential for cytochrome P-450 activity (Kaplan and Finlayson 1981). Another important aspect of diet and chemical toxicity, is in the need for folate in drug metabolism and chemical detoxication, and the particular needs of patients on chronic drug adminstration, especially where the drugs are potent enzymeinducing agents, such as phenobarbitone and diphenylhydantoin. Administration of these drugs to institutionalized epileptics receiving a poor diet, resulted in a low folate status within a year or so, which led to loss of drug detoxication ability, hyperchromic anaemia and teratogenic effects in the offspring. Subsequent studies on experimental animals confirmed these findings, namely, the drug-induced enzyme induction increases in the dietary needs for folate which, if not met, can


391


result in toxicity due both to impairment of drug detoxication and to insufficient folate for normal physiological needs. Chemicals which are inducers of cytochrome P-450 may also affect vitamin D activity, as this vitamin is activated by P-450 metabolism (Hahn and Avioli 1984). Minerals Iron is essential for the formation of haem, the cytochromes P-450, and mixedfunction oxidation, but iron deficiency does not decrease P-450 nor mixed-function oxygenase activity; excess iron, however, enhances the formation of reactive oxygen species, lipid peroxidation, membrane damage and destruction of P-450 (Wills 1972). Iron catalyses microsomal oxygen radical generation, the critical locus of which appears to be NADPH-cytochrome P-450 reductase (Cederbaum 1989a), and it is also possible that iron per se, as oxygen-bridged ferrous-ferric complexes may initiate lipid peroxidation (Minotti and Aust 1989). Dietary supplementation of iron enhanced the promotional phase of 1,2-dimethylhydrazine-induced colorectal cancer in rats, which was reveresed by phytic acid, a component of dietary fibre, probably due to the chelation of the iron by the phytic acid, with the consequent diminution of the ability of the iron to generate oxygen radicals (Nelson et al. 1989). Selenium is essential for the protective effects of glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) against oxygen radicals and lipid peroxidation. A Se-deficient diet therefore increases lipid peroxidation, and in consquence increases the degradation of the cytochromes P-450, with impairment of cytochrome P-450 induction by phenobarbitone (Wrighton and Elswick 1989); conversely, selenobetaine at 1-2 ppm in the diet decreased the incidence of DMBA-induced rat mammary tumours by 25-50% (Ip and Ganther 1990). Magnesium increases the liver microsomal contents of cytochrome P-450, cytochrome P-450 reductase, and hydroxylase activities, possibly protecting against oxidative damage by maintaining glutathione concentration, as it does in erythrocytes (Hsu et al. 1982). Other food components Alcohol is essentially a carbohydrate source of calories devoid of other valuable nutrients; in moderation it is socially enjoyable but in excess can promote oxidative stress and hepatotoxicity by the induction of cytochrome P450IIE1, the production of oxygen radicals and lipid peroxidation (Cederbaum 1989b). This alcohol-inducible form of P-450 has a high potential to activate drugs and xenobiotics to toxic reactive intermediates, thereby explaining the susceptibility of the alcoholic to adverse drug reactions, hepatotoxicity and carcinogenesis (Lieber 1990). Chronic ethanol feeding to rats caused marked losses in hepatic vitamin E which indicate that the combination of alcohol and low dietary vitamin E intake renders the liver more susceptible to oxygen radical attack (Kawase et al. 1989). The flavonoids, a large group of naturally occurring compounds found in fruit and vegetables, have been associated with protection against hepatotoxicity; catechin and silybin have been shown to be effective antihepatotoxins and are thought to act by preventing lipid peroxidation or by stabilizing biological membranes (Davila et al. 1989) Monoterpenoids, such as cMimonene and menthol have been shown to be anticarcinogenic and menthol has been shown to inhibit the

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DMBA-initiation of rat mammary tumours (Russin etal. 1989). Similarly, cruciferous vegetables contain a variety of anticarcinogenic compounds, including the glucosinolate of indole-3-carbinol which inhibits polycyclic aromatic hydrocarbon-induced carcinogenesis by a mechanism as yet unknown (McDannell etal. 1988). Human foods also contain a range of potent genotoxic compounds, especially the mutagenic carcinogenic heterocyclic amines derived from fried meat (Sugimura 1985). The mutagenicity of foods appears to depend on the cooking method and fried or flame-broiled foods are 10-fold more mutagenic than boiled or baked foods (Doolittle et al. 1989). Conclusions It thus appears that, for effective protection against environmental chemicals and reactive oxygen species, all categories of food nutrients are essential. Without these natural detoxication systems against toxic chemicals and oxygen radicals, survival itself becomes threatened. Protection against chemical toxicity, and hence survival, is therefore probably the most important role of food and nutrition. Detoxication proceeds even at the expense of many other physiological functions; for example in fasting conditions when glutathione is limited, the administration of bromobenzene to rats resulted in incorporation of the chemical, detoxicated as a cysteine derivative, into the body fur (Spencer and Williams 1950). Genetic evidence of the evolution of the cytochrome P-450 superfamily, and of the evolutionary warfare between plants and herbivores in the process of coevolution which has resulted in the development of animal detoxication systems, also give testimony to the importance of detoxication in the survival of animals species (Gonzalez and Nebert 1990). Although metabolism of chemicals by the various P-450 families generally results in detoxication, the converse process, namely metabolic activation resulting in toxicity, mutagenicity, or carcinogenicity, may also occur (Parke 1987). It is now realized that certain families of P-450 are associated with activating monoxygenation, and only those chemicals that are specific substrates of these enzymes are likely to exhibit overt toxicity (Parke et al. 1988). The major family of these enzymes associated with metabolic activation is the P450I family, which oxygenates polycyclic aromatic hydrocarbons, aromatic amines, and other planar molecules, by catalysing conformationally-hindered oxygenations to yield reactive intermediates, which interact with vital cellular components as these reactive intermediates are resistant to conjugation and detoxication (Ioannides et al 1984). A second activating family is that of P450IIE, which tends to produce oxygen radicals, that oxygenate substrates (e.g. ethanol, diethyl ether, benzene) of this enzyme family, and simultaneously result in oxygen toxicity (Ekstrom and Ingelman-Sundberg 1989). These two families of P-450 are normally present at low levels in tissues but can be markedly increased by enzyme induction (Parke and Ioannides 1990), effected in the case of P450I by ingestion of typical substrates, such as the food pyrolysis mutagens (Sugimura 1985), and in the case of P450IIE by the ingestion of large amounts of ethanol, or by fasting (Hong etal. 1987). Consequently, certain food components can direct metabolism away from detoxication to activation, toxicity, and carcinogenicity, and conversely, from toxicity to detoxication (Ames 1983). Currently, the public and some members of the medical profession, are obsessed


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