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BIOCHEMICAL GENETICS OF

.6107

INSECTICID E RESISTANCE 1,2 Frederick W. Plapp Department of Entomology, Texas A&M University, College Station, Texas 77843

Research on insecticide resistance has fallen into some disfavor among entomolo­ gists in recent years. This may be a response to the realization of the potential for environmental disruption that followed the massive introduction of insecticides into the global ecosystem. There is also a developing interest in solving pest problems through the use of more insect-specific chemicals that may generate less severe resistance problems. However, growing awareness of the imminent population-food crisis has caused a reawakening to the need for pest control by whatever means practical. Based on this awareness, the needs for understanding the mode of action of insecticides as well as the biochemical and genetic bases for resistance are greater than ever. In this review, it is assumed the reader understands basic genetics and the need for using genetical methods before undertaking biochemical studies of insecticide resistance. Excellent reviews by Oppenoorth (83) and Tsukamoto (142) have clearly defined necessary genetic methodology. No changes seem necessary for approaching the more classical Mendelian aspects of the genetics of resistance. At a molecular level the problem is more complex. The latter area is discussed briefly in the closing section of this paper. ALTERED ACETYLCHOLINESTERASE Entomologists have long suspected that a change in the target enzyme acted on by an insecticide would be the ultimate resistance mechanism. Although the hypothe­ sis may be true, evaluation is possible only when we have some understanding of the biochemical target of an insecticide. Therefore, we are limited to investigations of organophosphates (OP) and carbamates, insecticides known to act on acetyl­ cholinesterase (AChE, E.C.3.1.1. 7), which presumably owe their toxicity to their effects on this enzyme. IThe survey of literature for this review was completed in February 1975. 2Approved for publication by the Director of the Texas Agricultural Experiment Station.

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Significantly, doubts have been expressed on whether inhibition of AChE is the actual mechanism of OP and carbamate toxicity in insects (80). Unlike in mammals, AChE inhibition in insects does not result in death by asphyxiation. Therefore, it is possible to argue that inhibition of the enzyme is not necessarily lethal in ins� cts. Besides, in earlier work there was not always a good correlation between AChE inhibition in. insects and OP poisoning (146). This objection was largely overcome by demonstrating that inhibition of thoracic AChE by OPs correlated better with poisoning than did inhibition of head AChE (10, 37, 71). The fact that changes in AChE sensitivity to inhibition by OPs and carbamates can confer high levels of resistance to these insecticides is indisputable evidence that AChE inhibition is a major factor in the toxic action of these chemicals on insects. Further, research in this area provides an excellent opportunity to define in detail the nature of the possible changes in a biologically indispensible enzyme that may occur and still allow it to function in a biochemically satisfactory manner. Another point of interest is that resistance due to an altered target enzyme arose later than resistance due to metabolic processes and changes in absorption rates. The latter types appear to be biologically preferred (or more available) as mechanisms for protection against xenobiotics. The first clear evidence of a change in AChE as a basis for resistance was provided by Smissaert's report (127) of a modified AChE, which was of decreased sensitivity to inhibition by OPs, in the Leverkusen strain of the red spider mite Tetranychus urticae. Findings of altered AChEs in other mite populations have been reported (8, 131, 146). In all cases studied (8, 127, 151), the altered AChE of resistant strains showed an unusually low ability to hydrolyze acetylcholine. It was later proposed (128) that the essential alteration of the enzyme was the slightly different position of an imidazole residue relative to the serine hydroxyl involved in the reaction. Other studies reported evidence for increased detoxification as an OP resistance mechanism in mites (51, 150), indicating that here, as in insects, changes in detoxifi­ cation rates are important resistance factors. Genetic studies have shown that in mites a single dominant gene is usually involved in resistance due either to altered AChE or to increased detoxification (6, 5 0, 5 1, 70, 121, 134). A report of a recessive OP resistance gene has appeared (26), but such resistance genes appear to be rare. Adequate tests of allelism are still needed, and biochemical mechanisms of increased detoxification remain largely unidentified. Findings of modified AChE were next reported from Australia in populations of the cattle tick Boophilus microplus (66, 109, 123). AChE from resistant strains hydrolyzed acetylcholine at about 10% of the normal rate. It was concluded that lower sensitivity of the enzyme to OP inhibition was sufficient to account for resistance in most strains studied (109). Later work (77, 78, 120) showed that AChE of both susceptible and resistant strains was composed of at least five forms. Three of the AChEs of resistant ticks were highly insensitive to inhibition by OPs. Early efforts to demonstrate a relationship between changes in AChE and OP resistance in insects gave equivocal results. For example, a population of the sheep blowfly Lucilia cuprina with 5 -fold resistance to diazinon had an AChE only 1.5

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times as resistant to inhibition by diazoxon as normal ChE (122). An even smaller (1. 2-fold) difference in sensitivity to phosphamidon was reported in a resistant strain of the Mediterranean fruit fly, Ceratitis capitata (159). Clear evidence for resistance based on an altered AChE in insects was first reported in 1971 by Hama & Iwata (49) in a population of the green rice leafhopper, Nephotettix cincticeps, resistant to carbamate insecticides. A second report (60) established that the altered enzyme was also important in OP resistance in this insect. AChE of resistant populations was 18-115 times less sensitive than normal to inhibition by carbaryl, propoxur, and malaoxon and was controlled by a single partially dominant gene. Evidence for an altered AChE in the house fly, Musca domestica. was first reported in a tetrachlorvinphos-resistant strain by Tripathi & O'Brien in 1973 (141). A similar report has also appeared on a dimethoate-resistant strain (25). The latter also gave results of genetic studies on inheritance of altered AChE resistance. The factor involved is a chromosome II gene, AChE·R, located about 20 map units from the visible marker aristapedia. In both resistant strains, a large decrease was found in the bimolecular rate constant, ki. for inhibition of AChE by various OPs. Data were presented (24a, 141) indicating that the major cause was a massive decrease in affinity between inhibitor and enzyme, which was partly offset by faster phospho­ rylation. Confirmation of chromosome II inheritance of altered AChE resistance has been obtained in my laboratory (F. W. Plapp, unpublished results). Evidence has recently been obtained for an AChE insensitive to inhibition by paraoxon and propoxur in two strains of Anopheles albimanus. the primary vector of malaria in Central America (7). The resistant populations were developed by selection pressure in the laboratory and do not represent a field situation. Neverthe­ less, these data are disturbing in terms of future malaria control projects. In both the house fly and the cattle tick, AChE is apparently composed of at least four isozymic forms that differ in sensitivity to inhibition by OP insecticides (32, 77, 78, 120, 140). Resistance may occur either because of a change in the relative amounts of the different forms or because of a change at the active site of one or more AChE isozymes. There is electrophoretic evidence that the AChE isozymes are interconvertible and probably represent different stages of aggregation (24a). DECREASED ABSORPTION A chemical can not very well be toxic if it does not enter a target organism. Therefore, rate of absorption of insecticides by insects is an important determinant of insecticide toxicity. Similarly, decreases in absorption rate that would have the effect of allowing more time for detoxification of insecticides would constitute an ideal defense mechanism. Some interesting genetic work in this area has been accomplished. Unfortunately, comparable biochemical data are lacking. It was long assumed that nonpolar insecticides penetrate insects more rapidly than polar insecticides. probably because of their greater affinity for epicuticular grease. The 1963 report by Olson & O'Brien (81) effectively demolished that hypoth­ esis by demonstrating unequivocally in Periplaneta americana that insecticide pen-

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etration into the pronotum from the waxy layer increased with polarity. This finding has since been confirmed many times. Perhaps c1e;lrest is the 1973 report by Szeicz et al (130), which demonstrates a direct relationship between the rate of absorption of four insecticides by larvae of the tobacco budworm, Heliothis virescens, and the relative polarity of the insecticides as measured by hexane: acetonitrile partitioning properties. A complicating factor in absorption studies comes from the research of Gerolt (47). He presented evidence based on autoradiographic studies with 14C-dieldrin suggesting that insecticides applied topically to insects spread laterally within the integument and then reach the site of toxic action through the tracheal integument. As discussed by Ebeling (30), contradictory evidence has been obtained and the matter seems far from settled. The availability of genetically purified house fly strains that differ in the rate at which they absorb insecticides (see below) offers a way to investigate the problem, although it has not been utilized so far. Early biochemical studies clearly relating decreases in insecticide absorption to resistance in the house fly were done with pyrethrins in a strain resistant to pyreth­ rins and DDT (40) and with diazinon in several OP-resistant strains (36, 41, 48). No metabolic data were reported in the pyrethrin study, but, in the investigations with diazinon, evidence was also obtained for increases in rates of insecticide detox­ ification. Relative importance of the two types of resistance factors was not deter­ mined. Genetic studies on decreased absorption as a resistance mechanism in house flies were possible only when suitable markers for the different chromosomes became available. The subject has been extensively investigated in recent years. Sawicki and associates in England concentrated on a multiresistant strain, SKA. Delayed penetration in SKA is controlled by a gene on chromosome III. It confers low levels of resistance to DDT, dieldrin, and diazinon (31, 115-117). The gene for delayed penetration was given the mutant symbol Pen. It works as an intensifier of resistance by allowing detoxification mechanisms a longer time in which to operate (110, 111, 118). The present author and R. F. Hoyer also studied the genetics of decreased absorption in house flies. The work started on resistance to organotin insecticides present in a strain that also has a very high level of resistance to parathion. From this strain, a chromosome III gene that confers resistance to organotin insecticides and intensifies parathion resistance was isolated and given the mutant symbol tin (57). Later work (104) showed that the tin gene acted to reduce rates of insecticide absorption. Figure I illustrates comparative rates of absorption of DDT and dieldrin by house fly strains possessing and lacking the tin gene. In a final study (58), evidence was obtained that tin interacted with a variety of major resistance genes to increase resistance to DDT, dieldrin, and various organophosphates. Flies possessing the tin gene were sent to Sawicki, who demonstrated that tin and Pen were allelic (110). Because reduced penetration is a more descriptive term for the phenomenon, it seems that use of the term penetration, mutant symbol Pen, would be most accurate in describing this resistance mechanism.

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DIELDRIN

DDT 2400

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1600

800

3

2

4

3

2

4

TIME OF EXPOSURE IN HOURS

Figure 1

Absoprtion of DDT and dieldrin by susceptible house flies (0

possessing the gene

tin (x

--

--

0) and flies

x) for decreased rate of insecticide absorption (104).

The decreased absorption of insecticides controlled by a chromosome III gene in house flies extends also to naphthalene vapors (19). Here the chromosome III gene was shown to increase the effect of an oxidative resistance gene on chromo­ some II. Malathion resistance in Aedes aegypti was found to be caused by decreased absorption (69). Further studies (95) indicated a probable relationship between decreased absorption and DDT resistance as well. The major genetic factor for decreased absorption in this insect is a chromosome III semidominant. Other genes were thought to be involved in resistance to both insecticides (95). Decreased absorption as a resistance mechanism has been demonstrated several times in the tobacco budworm, an important cotton pest in the southern United States. Decreased absorption of endrin (07), DDT (92), and fenitrothion (99) by larvae of resistant strains has been reported. Biochemical studies demonstrated higher lipid and protein content in the cuticle of slow-absorbing larvae and sug­ gested that ascorbic acid influenced cuticular properties and resistance (148). In this connection, it is well to note a 1961 report (44) demonstrating that the greater tolerance to insecticides of mature as compared to immature larvae of the corn earworm, Heliothis zea, appears to involve a decrease in absorption rate. No bio­ chemical basis for the observed effect was given. RESISTANCE TO INSECT GROWTH REGULATORS Materials covered in this section include juvenile hormone analogs (JHAs) and a substituted benzoylphenylurea, which acts by interfering with cuticle deposition. Limited information available indicates insects can become resistant to these chemi­ cals in much the same way they do to insecticides.

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Earlier, it was suggested that resistance to juvenile hormones (JHs) and JHAs would not occur. The basis for this statement is that an animal ought not to become resistant to its own hormones (ISS). The hypothesis of nonresistance becomes untenable simply by comparing JHAs with OP insecticides. With OP insecticides, most cases of resistance relate to increased detoxification and/or decreased absorp­ tion. Since insects undoubtedly possess enzymatic capabilities for regulating levels of their own hormones, resistance can arise the same way it does to standard insecticides. This observation is supported by the fact that most JHA-resistant insects were previously resistant to insecticides. Resistance to JHAs-at least to date -is actually cross-resistance as a result of selection of insect populations through the use of other xenobiotics. Such resistance implies the modes of detoxification for JHAs and insecticides are similar. The first evidence of resistance in insects to a JHA was the 1972 report by Dyte (27) of an approximate 3-fold tolerance to methyl 10, 1 1-epoxy-7-ethyl-3, 1 1, dimeth­ yl-2, 6-tridecadienoate in a strain of the red flour beetle, Tribolium castaneum. that was resistant to many insecticides. Reports of low-level cross-tolerance to one or more JHAs in house flies (l8, 6 1, 106) and the tobacco budworm (9) followed. Slight cross-resistance (l. 4-fold) to a JHA was reported in Czechoslovakia in a malathion­ resistant strain of the aphid Therioaphis maculata (59). The same study reported evidence for the slightly increased effectiveness of another JHA against the malath­ ion-resistant strain as compared to a susceptible strain. Recently, resistance to several JHAs was induced in a laboratory population of Culex pipiens pipiens apparently susceptible to insecticides (13). This report may represent the first exam­ ple of a pure JHA resistance. Recent studies have provided evidence that, in the house fly, increased oxidative detoxifying activity is responsible for cross-resistance to JHAs. In one series of tests (106), resistance to JHAs occurred only in a strain with high levels of oxidative detoxifying enzymes (105). Susceptible strains and strains with other resistance mechanisms were susceptible. In another study (149) the inheritance of resistance to the JHA methoprene was investigated in a cross between the high-oxidase Rutgers R-diazinon strain and a susceptible strain carrying the markers stubby wing, brown body, and ocra eye. Tests with larvae of the backcross of FI flies to the susceptible parent showed that resistance to the JHA was controlled by a gene (or genes) on chromosome II and thus is linked to, if not identical to, the chromosome II high-oxidase gene already known to be present in the Rutgers R-diazinon strain (133). More recently, Cerf & Georghiou (l9) reported that comparisons of JHA toxicit­ ies to a number of OP-resistant house fly strains suggested that mixed-function oxidases play an important role in detoxifying JHAs and presumably in resistance to them. Another report by the same authors (20) demonstrated that insecticide-resistant house fly strains are resistant to TH 60-40, an insect growth regulator that acts as an inhibitor of chitin synthesis in insect larvae. Biochemical mechanisms responsible for resistance in the tested house fly strains were not specified, and therefore the

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resistance mechanism cannot be defined. However, it seems likely that, as with JHAs, increased degradation of the chemical via oxidative processes is the probable resistance mechanism.

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RESISTANCE TO PYRETHROIDS Use of pyrethroids as insecticides is presently undergoing a great expansion. Pyre­ throids possess many desirable properties, including high toxicity to insects, low toxicity to mammals, and high biodegradability. Renewed interest in these naturally occurring insecticides has been accompanied by the development of many synthetic pyrethroids showing a wide range of insecticidal properties (33, 76). Genetic and biochemical studies have contributed greatly to our understanding of pyrethroid resistance in insects. Data presently available should prove very useful in evaluating future possibilities for use of these chemicals as insecticides. Early research on resistance to pyrethrins repeatedly pointed out the close rela­ tionship between resistance to paralysis by DDT (knockdown resistance) and resis­ tance to pyrethrins in house flies (15 , 39), ticks (152), human body lice (23), and other insects. Key points in understanding this relationship include the report by Blum & Kearns (12) of a negative temperature coefficient for pyrethrins, just as is the case with DDT, and the demonstration by Tsukamoto et al (144) of decreased nerve sensitivity to poisoning by DDT in strains that combine resistance to DDT and pyrethrios. Unfortunately, there a'ppear to be no similar studies 00 the relative sensitivity to pyrethrin poisoning of susceptible and resistant insect strains, although the effect of pyrethroids on insect nervous tissue has been carefully measured (75). The gene(s) conferring DDT and pyrethrins knockdown resistance (kdr) have long been known to be recessive in the house fly (15, 143). Demonstration of the probable allelism of the two apparently distinct types of resistance was accomplished (103). Recessive gene(s) on chromosome III that conferred resistance to either DDT or pyrethrins were introduced into strains with mutant markers controlled by genes on the same chromosome. Each population so prepared was resistant to both types of insecticide, indicating that the genes are either allelic or very closely linked. In the same study, evidence was obtained that resistance to DDT and pyrethrins in the mosquito Culex tarsalis is controlled by the same gene. In C tarsalis, as in the house fly, resistance extends to both pyrethrins and pyrethrins-piperonyl butox­ ide combinations. By way of contrast, pyrethrins resistance in the German cockroach, Blatella germanica, was found to be inherited as a simple, incompletely dominant trait located in linkage group VI (22). The inheritance of this trait is independent of that for DDT resistance, and therefore the trait is not of the kdr type. More detailed genetic and biochemical studies on pyrethroid resistance have been recently reported by Farnham and associates at Rothamsted (34, 35, 38). In an initial study (34), a pyrethrins-resistant strain was divided into two subtrains, one selected with natural pyrethrins and the other with resmethrin. Selection with the former resulted in higher resistance to all pyrethroids tested. In that study and in

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a later study that utilized crosses between resistant strains and mutant-marked susceptible strains (35), Farnham isolated four distinct genes that confer resistance to pyrethroids. One of these appeared to be a chromosome III gene, identical to kdr. Another chromosome III gene, Pen, was for reduced penetration. Two other genes were identified: py-ses on chromosome V, which is sesamex-suppressible, and py-ex on chromosome II, which is not affected by synergists. The possible allelism of these genes with other chromosome II and V resistance genes was not investi­ gated. In a more recent study (38), evidence was presented that selecting OP­ resistant house flies with synthetic pyrethroid-synergist combinations gave less resistance than selecting with pyrethroids only or with a natural pyrethrins-syner­ gist combination. These results may be of practical signifiance in determining future pyrethroid use patterns. A final point concerns the relationship between the type of metabolism undergone by pyrethroids and resistance. Several studies (21, 157, 158) have clearly shown that oxidative detoxification is the primary metabolic pathway for most pyrethroids, both natural and synthetic. Such metabolism can be largely blocked by antioxidant synergists. On the other hand, certain pyrethroids derived from primary alcohols are metabolized by esterases (1, 2). Esterase-inhibiting organophosphates such as s,S,S-tributylphosphorotrithioate strongly synergize such materials. Apparently nothing is known about resistance to those pyrethroids that are metabolized by esterases. Surprisingly, in view of the fact that pyrethroids are easily degraded, increases in metabolism are not of primary importance in resistance. For example, the genes py-ses and py-ex, described by Farnham, confer less resistance than do Pen and kdr. Pen involves decreased absorption. Kdr is not a detoxification gene; more likely, it involves a change in target site of pyrethroid-DDT action against the insect nerve. If so, this is a case of biochemical and genetic studies showing that vastly dissimilar insecticides may have similar, if not identical, modes of action. METABOLIC RESISTANCE TO ORGANOPHOSPHATES AND CARBAMATES In 1965 , when the previous review of this subject was written for the Annual Review of Entomology (83), virtually nothing was known about resistance to carbamate insecticides, and only one resistance mechanism for OPs had been identified. This was the so-called altered ali-esterase mechanism in which esterase normally inhib­ ited by OP-oxons is changed to a form capable of oxon degradation. Since 1965 a tremendous amount of biochemical and genetic data has been generated relating to resistance in the house fly and in other insects. Other major resistance mechanisms involving detoxification are the NADPH-dependent mi­ crosomal mixed-function oxidase system, which confers resistance to both OPs and carbamates, and the glutathione-dependent alkyl and aryl-transferase system, which appears to be involved only in resistance to OPs. To summarize, all known mechanisms of detoxification of OPs and carbamates are also mechanisms of resistance. They confer resistance by occurring at abnor-

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mally high levels in resistant strains. All are inherited as if controlled by simple semidominant genes, even when they appear to involve complex series of biochemi­ cal changes. Beyond this, little is known about the nature of the genes involved. Within the limits of this paper, detailed discussion of various metabolic pathways and their relationship to resistance is not possible. The reader is referred to several excellent reviews dealing with insecticide detoxification and resistance mechanisms (5, 17, 24, 52-54, 63, 64, 74, 94, 138, 154). Other reviews deal more specificially with genetic aspects, including inheritance of resistance and interactions between resis­ tance genes (45, 46, 96, 100, 112, 113, 142). The use of synergists to block resistance mechanisms has also been reviewed (85, 86). Carboxylesterase

The involvement of carboxylesterase (E.C.3.1.1.1 aliesterase hydrolase) in resistance dates back to the finding (11, 147) of abnormally low ability to hydrolyze methyl n-butryate and certain other aliphatic and aromatic esters in homogenates of a number of OP-resistant house fly strains. The factor was named a (for altered ali-esterase) by Oppenoorth and associates (83). A similar finding was reported later for a malathion-resistant blowfly, Chrysomya putoria (139). However, the above insects seem anamolous in the matter of low ali-esterase activity. Many other insects with esterase involvement in OP resistance appear to have unusually high levels of carboxylesterases, as measured by a variety of tech­ niques including substrate hydrolysis in vitro and polyacrylamide gel electrophore­ sis. These include Culex tarsalis (68), Dermestes maeulatus (28), Tribolium castaneum (29), Heliothis virescens (14, 153), Myzus persicae (75a, 129), Nephotettix cinetieeps (90), and Laodelphax striatellus (90, 91). Studies on the genetics of insect populations with changed types or amounts of carboxylesterase indicated that resistance and enzyme activity are controlled by a single semidominant gene. This was shown for the house fly (42, 55, 82) and for Culex tarsa/is (102). In the house fly, the gene is on chromosome I I . The mechanism of resistance seems to be an increase in ability to degrade the AChE-inhibiting oxygen analogs of phosphorothioate insecticides (83) and/or an increase in ability to degrade malathion via carboxylester hydrolysis (86, ISla). Resistance of this type can often be blocked by a variety of synergists, primarily tris-substituted noninsecticidal OPs (96). =

=

Glutathione-Dependent Alkyl and Aryl Transferase

Occurrence of glutathione-dependent metabolism of OP insecticides was first clearly demonstrated by Fukami & Shishido (43, 126) who studied the dealkylation of various OP insecticides. The work followed earlier studies showing dealkylation of OPs by insects in vivo (101). The occurrence of high levels of glutathione-dependent detoxifying enzymes has been reported in resistant house flies (67, 67a, 73), and in OP-resistant tobacco budworms (14). Another report (72) demonstrated high levels of the system in an OP-resistant predaceous mite. Genetic studies revealed that high levels of glutathione-dependent OP metabolism in house flies are controlled by a chromosome II gene (67a). This was confirmed in

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a subsequent study (89) in which the gene was named g. It is noteworthy that no one has yet prepared an insect strain containing only this resistance mechanism and no others, a necessary prerequisite for adequate evaluation of the significance of the resistance mechanism.

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NADPH-Dependent Microsomal Oxidase

At least two genes in the house fly are known to control high levels of microsomal oxidase activity. Both are semidominant in inheritance and both confer resistance to extremely wide ranges of insecticides. Resistance associated with them can often be blocked by methylenedioxyphenyl and other antioxidant synergists (86, 96). Gene(s) on chromosome V, known variously as Ses (114), DDT-md (88), or Ox-5 (62), confer oxidative resistance to many OPs, carbamates, and DDT. Chromosome II high-oxidase gene(s), with the mutant symbol Ox-2 (62), confer resistance to most OP and probably to nearly all carbamates, but not to DDT. Chromosome II oxidase genes seem more common in resistant house flies than chromosome V genes (84, 142, 145). However, several genetic studies indicated some oxidative resistance contribution of both chromosomes II and V in different resistant house fly populations (97, 105, 119, 133). Apparently only oxidative genes confer metabolic resistance to carbamate insecti­ cides in the house fly. This contrasts with OPs, in which both oxidative and nonox­ idative metabolic resistance genes are known to be important. Both genetic factors relate to a variety of changes in total microsomal oxidase activity. These include increases in the quantity of cytochrome P-450, the terminal oxidase of the mixed-function oxidase system, as well as several types of qualitative changes in P-450. Among the latter are changes in carbon monoxide absorption maxima and changes in several types of substrate difference spectra (4, 16, 53, 93, 132, 133). It remains unclear how such a large variety of biochemical changes can be controlled by such a limited number of resistance genes. High levels of microsomal oxidase characterize several other OP and carbamate­ resistant insects, including the tobacco budworm (14, 99, 108, 156) and the cabbage looper Trichoplusia ni (65). In the tobacco budworm at least, the oxidative mecha­ nism seems similar to that attributed to the chromosome V house fly gene in that it is associated with both DDT and OP metabolism (99). The same or similar resistance mechanisms probably occur widely, but so far they have not been identi­ fied. Interaction 0/ Resistance Genes

In the house fly all OP and carbamate detoxification resistance mechanisms, with the single exception of Ox-5, are controlled by genes on chromosome II. Apparently these genes are fairly closely linked. Crossover data on the location of gene a and gene Ox-2 in relation to severalJmarkers has been reported (55 , 62), with somewhat contradictory results. Another report (42) stated crossovers between gene a and several chromosome II markers were "either rare or completely absent." No data are available on the location of gene g on chromosome II. Biochemical studies on resistance have often dealt with only one of these genes. The possibility of other genes being present in test populations was either not known

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at the time or simply ignored. Consequently, we have a poor understanding of the actual resistance associated with each of these genes. Detailed genetic studies such as those being utilized by Sawicki (112, 113) are necessary to determine how much resistance is caused by which gene. It seems likely that most resistance genes in the house fly confer only weak or moderate resistance to OPs and carbamates. High resistance levels usually occur only in the presence of multiple resistance genes. Simi1�rly, OP--

Biochemical genetics of insecticide resistance.

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