Chem.-Biol. Interactions, 28 (1979) 71--81 © Elsevier/North-Holland Scientific Publishers Ltd.

71

COMPARISON OF THE INTERACTION OF TRICYCLIC ANTIDEPRESSANTS WITH HUMAN P O L Y M O R P H O N U C L E A R LEUKOCYTES AS MONITORED BY THE G E N E R A T I O N OF CHEMILUMINE SCENCE

M.A. TRUSH *, M.J. REASOR, M.E. WILSON **, K. VAN DYKE Department of Pharmacology and Toxicology, West Virginia University Medical Center Morgantown, WV 26505 (U.S.A.) (Received July 24th, 1978)

(Revision received June 4th, 1979) (Accepted June 17th, 1979)

SUMMARY

The interaction of imipramine with human polymorphonuclear leukocytes (PMNs) results in a chemiluminescence (CL) response which has been attributed to the electronic excitation of the imipramine molecule resulting from a reaction of the drug with reactive oxygen species. In order to determine what portion of the tricyclic molecule is involved in this reaction, the interaction of other tricyclics with PMNs was monitored by chemiluminescence. It was observed that tricyclic antidepressants having a carbon atom at position 5 of the ring moiety (amitriptyline, for example) did n o t yield CL with either resting or zymosan-activated PMNs. In fact this group of c o m p o u n d s inhibited the zymosan-induced CL response. However, CL was observed, with both resting and metabolically-activated PMNs, from several tricyclics having a heterocyclic nitrogen at position 5. These included imipramine, desipramine, opipramol and iprindole. Chlorimipramine, which has a chlorine atom at position 3 of the ring system, failed to yield CL with resting or stimulated cells. Similarly, imipramine N-oxide failed to yield CL with resting cells, but enhanced CL was observed with zymosan-activated PMNs. On the basis of these observations it appears that some aspect of the ring moiety, other than just a heterocyclic nitrogen, facilitates a r e a c t i o n between these molecules and reactive oxygen which culminates in the generation of CL. Abbreviations: CL, chemiluminescence; IPNO, imipramine N-oxide; ~O2, singlet oxygen; O~, superoxide anion ; BP, benzo[a ]pyrene; MPO, myeloperoxidase. * Present address and address for correspondence: Laboratory of Toxicology, National Cancer Institute, NIH, Bethesda, MD 20205, U.S.A. ** Present address: Dept. of Immunopathology, Scripps Clinic and Research Foundation,

LaJolla, CA 93037, U.S.A.

72 INTRODUCTION The utilization of molecular oxygen by cells often results in the generation of reactive forms of oxygen which can participate in the biochemical processes of the cell [1]. These reactive forms of oxygen include the superoxide anion (05), hydrogen peroxide (H202), the hydroxyl radical (-OH), and electronically excited singlet molecular oxygen (IO2). Singlet oxygen can dissipate its excess energy by photon emission (chemiluminescence), thermal decay or by IO2-mediated reactions which can also result in chemiluminescence (CL). As such, measurement of CL represents a possible means by which to monitor and detect both the generation of and reactions mediated by 02 and 102. A cell type presently being investigated for its ability to generate both reactive oxygen species and CL is the human polymorphonuclear leukocyte (PMN). Allen et al. [2] initially demonstrated that PMNs generated CL in response to phagocytizable particles. Subsequent reports have advanced the concept that this CL is a reflection not only of the generation and relaxation of electronic excitation states, such as 10~ and/or excited carbonyl groups, but also of an interaction between the stimulating particle and the reactive oxygen species produced by the metabolically activated cell [3,4]. The generation of this CL by PMNs is dependent upon the ability of the cell to produce both O~ and H202 and the interaction between myeloperoxidase (MPO), H202 and C1- [4,5]. The MPO-H2OvC1- system has recently been shown to produce 102 as indicated by the conversion of 2,5-diphenylfuran to cisdibenzoylethylene [6]. Further support that phagocytizing PMNs do in fact generate 102 has recently been provided by Fong et al. [7]. Chemicals have also been shown to be activated upon interacting with the reactive oxygen generated by both resting and metabolically activated PMNs. The cyclic hydrazide luminol is capable of being oxidized and yielding CL upon interaction with resting PMNs; however, this CL is greatly enhanced when the cells have been metabolically stimulated to generate increased levels of reactive oxygen [8]. Similarly, estradiol has been shown to be irreversibly bound to macromolecules of the PMN during interaction with phagocytosing PMNs [ 9]. This binding of estradiol to the PMN is dependent on the capability of the cell to generate O5 and H202 and the activity of myeloperoxidase, the enzyme responsible for 102 formation. We have been investigating an interaction between the tricyclic antidepressant imipramine and human PMNs which manifests itself as a chemi, luminescence response [10]. Similarly, addition of imipramine to a cell-free reactive oxygen generating system, xanthine oxidase-purine, resulted in CL. While CL is observed following addition of imipramine to resting PMNs, this response is much greater if the cells are or have been metabolically activated by an opsonized particle (zymosan). The interaction of imipramine with resting PMNs failed to stimulate superoxide release indicating that this CL response from imipramine probably does not result from metabolic

73 9

6

I0 II

I

[ 4 /all3 CH2-CH~,-CH2-N \CH 3

Fig. 1. Illustration of numbering of the ring moiety of imipramine.

activation of the cell [11]. These observations support the contention that following the interaction with some form(s) of reactive oxygen the imipramine molecule undergoes a reaction which results in the generation o f CL. It appears that in addition to O5 and H202, the enzyme myeloperoxidase (MPO) and/or a p r o d u c t of its activity enhances this reaction. Tricyclic antidepressant molecules consist of a basic amine group attached via a short side chain to a hydrophobic ring moiety. A major structural difference between tricyclics is the atom at position 5 of the ring moiety (N vs. C) (Fig. 1). The purpose of the present investigation was to examine the interaction of various tricyclic analogs with both resting a n d activated cells in order to determine what structural c o m p o n e n t is invovled in the generation of CL from this drug-cell interaction. Preliminary experiments have led us to suggest that a heterocyclic nitrogen at position 5 may be necessary for CL to result [ 12]. MATERIALS

AND METHODS

Cell isolation. Blood was obtained from normal, healthy volunteers. PMNs were isolated b y dextran sedimentation as previously described [ 10,13 ]. Mesurement o f chemiluminescence. CL responses were monitored using an ambient-temperature liquid scintillation spectrometer (Packard, Model 2002) operated in the out-of-coincidence mode. The counter was set as follows: gain 100%, w i n d o w A -oo with discriminators set at 0--1000 and input selector 1 + 2. To begin the procedure, 1 ml of cells (5 × 106 PMNs) was incubated in 2--3 ml of Dulbecco's phosphate buffered' saline for 15 min at 37°C in previously dark-adapted polyethylene vials. After determining the background CL of each vial, opsonized zymosan (4 mg) and/or drug (final concentration 1 × 10 -4 M) was added (final volume 5 ml) to initiate the reaction and CL monitored for 0.5 min at 5-min intervals. Zymosan was prepared as previously described [10]. The vials were maintained at 37°C between countings. All additions t o the vials as well as the CL counting procedure were performed in a darkened room. The results are expressed as counts per unit time minus background values. Data are presented as peak (maximum) responses and temporal (time course) curves.

74 Statistical significance was determined by paired analysis [14]. Values were considered significant i f P < 0.05. Materials. The dextran (100 00{~-200 000 mol. wt.) and zymosan used in these experiments were obtained from Sigma Chemical Co. Drugs were generously supplied by the following companies: CIBA-GEIGY Corp. (imipramine, chlorimipramine and opipramol); Wyeth Laboratories (iprindole); Merck and Co. (amitriptyline and protriptyline); USV Pharmaceuticals (desipramine); Dumex Co. (imipramine N-Oxide); and Bayer (noxiptiline). RESULTS

Comparison of the CL responses of various tricyclic analogs. Previous observations with activated PMNs and a cell-free enzyme system suggested that some component of the imipmmine molecule was interacting with reactive forms of oxygen and as a result of this interaction a reaction occurred which was demonstrated by the generation of CL [10]. This study was undertaken to try to define what component of the tricyclic molecule, the ring moiety or the aliphatic side chain, is involved in this reaction. Figure 2 depicts the structures and lack of a CL response, when added COMPOUND (IxIO-4M)

AMITRIPTYLINE

STRUCTURE

~

DRUG RESPONSE

NONE

PEAK CL OBSERVED WHEN ADDED SIMULTANEOUSLY WITH ZYMOSAN(4rag)* (COUNTS/O,5 MIN+-.SEM(N)) 124,431+-3,043 (4)

II

CH-(CH2)2-N(CH3) 2 PROTRIPTYLINE

@

NONE

72,428 + 6,410(4)

H (CH2)3-NH(CH3) DOXEPIN

~

NONE

92,345 +--2,412(4)

II

CH-(CH2)2-N(CH3) 2

NONE

NOXlPTiLINE

184,420 + 10,213(4)

N-O-(CH2)2-N(CH3) 2 * ZYMOSAN

R E S P O N S E ',212,472+-20,542 (4)

Fig. 2. Peak chemiluminescence observed following the separate and simultaneous addition of tricyclicshaving a carbon atom at position 5 of the ring moiety to 5 x 106 PMNs. 'None' indicatesthat no C L above background was observed.

75

to resting PMNs, o f those tricyclic antidepressants having a carbon atom at position 5. In contrast, CL was observed when imipramine, desipramine, opipramol and iprindole were added to resting PMNs but not chlorimipramine and imipramine N-oxide (IPNO), a metabolite of imipramine (Fig. 3). Figure 4 illustrates the time course of the response by those tricyclics which yield CL when added to resting cells. Iprindole peaked by 1 min with opipramol, imipramine and desipramine each peaking at different times. Besides yielding CL with resting cells, increased CL was observed when imipramine was present during cellular activation by opsonized zymosan [ 10]. This was attributed to the increased reaction of imipramine with the reactive oxygen resulting from the metabolic activation of the cell. In addition to imipramine, increased CL was observed when opipramol, desipramine, IPNO and iprindole were added to the PMNs simultaneously with zymosan (Table I). As with resting cells, the more planar compound COMPOUND ( IxlO-4 M)

STRUCTURE

PEAK CL RESPONSE (COUNTS/0,5-+SE(N))

IMIPRAMINE

~ ' r

195,640:tl3,436 (5) (CH2)3-N{CH3)2

DESIPRAMINE

~L.%~LNI/J~

138,240:1:11,562(5)

(CH2)3-NHCH3 OPIPRAMOL

~

275,420::1:13,242(5) J

(CH2)3-N _jN-(CH2)20H

IPRINDOLE

~

47,520+5,431 (5) i

(CH2)3-N(CH3)2 CHLORIMIPRAMINE

[

2,042+-140(5)

~~L.c,i i

(CH2)3-N(CH3)2 IMIPRAMINE N-OXIDE

L I~.,.JL./~

2,842±89(5)

i

(CH2)3-N(CH3)2 J.

0

Fig. 3. Chemiluminescence generated following the addition of tricyclicshaving a heterocyclic nitrogen at position 5 of the ring moiety to 5 × 10 6 P M N s .

76 3,0

'o

2,5

x Z u'3

,5

2,0

, (,/') I-Z

o (.) .W (,..) Z W

o~ W Z

1.5 •

1,0

._1 W T (..)

0,5

o

2'0 2's 3'o

4'0

45

50

55

60

TIME OF RESPONSE (MINUTES) Fig. 4. T e m p o r a l r e s p o n s e curve o f t h e c h e m i l u m i n e s c e n c e g e n e r a t e d f o l l o w i n g the a d d i t i o n o f o p i p r a m o l , i m i p r a m i n e , d e s i p r a m i n e a n d i p r i n d o l e (1 x 10 -4 M final concent r a t i o n ) t o 5 x 106 PMNs. D a t a are f r o m a single e x p e r i m e n t w h i c h is r e p r e s e n t a t i v e oi five e x p e r i m e n t s , o, o p i p r a m o l ; o, i m i p r a m i n e ; =, d e s i p r a m i n e ; o, i p r i n d o l e .

TABLE I PEAK CL RESULTING FROM THE SIMULTANEOUS ADDITION OF HETEROCYCLIC N - C O N T A I N I N G T R I C Y C L I C S (1 x 10 -4 M) A N D Z Y M O S A N ( 4 mg) All s i m u l t a n e o u s r e s p o n s e s were s i g n i f i c a n t l y d i f f e r e n t (P < 0 . 0 5 ) f r o m z y m o s a n alone. Additon to PMNs (5 X 106 )

Peak CL response (counts/0.5 rain)

T i m e of peak response

Zymosan (Z) Z + Opipramol Z + Imipramine Z + Desipramine Z + Imipramine N-Oxide Z + Iprindole Z + Chlorimipramine

190 4 843 2 436 830 662 264 38

5 5 5 5 5 15 10

a M e a n + S.E.M; N = 5.

330 102 050 625 740 972 640

-+ 10 4 3 3 a +- 2 0 9 4 3 1 +- 38 4 2 0 +- 32 4 2 7 +- 61 324 + 13 240 +4215

77 opipramol produced the greatest effect. Except for iprindole this simultaneous peak response occurred at the same time as the peak zymosan response (5 rain). Iprindole reacted much slower and to a lesser extent with activated cells than the other compounds while chlorimipramine did not respond at all. In fact chlorimipramine, like the dibenzocyclopentadiene compounds (Fig. 2), inhibited the zymosan-induced CL. While not reacting with resting cells, IPNO gave strong CL with activated cells. The reason for this differential response is unknown. One possible explanation may be related to the structural features of this molecule. It has been shown that tricyclic antidepressants with a basic aliphatic side chain readily accumulate and bind reversibly in cells and tissues. In contrast, IPNO with its N-oxide moiety does not as demonstrated by the minor binding of this compound, as compared to imipmmine to a rat liver particulate fraction [15]. This inability of IPNO to associate closely with cells may account for the difference in reactivity seen with resting and activated PMNs (Fig. 3, Table I). DISCUSSION

Evidence has accululated recently that reactive states of oxygen can interact with xenobiotics leading to molecular activation, often followed by covalent binding to macromolecules [16,17] and/or chemiluminescence [18--20]. For example, Hamman and Seliger [20] have observed that addition of benzo[a]pyrene to liver microsomes of 3-methylcholanthreneinduced rats results in a chemiluminescence response which correlated with the hydroxylation of the parent compound. In addition, they proposed that the kinetics of the CL response was consistent with the production of an epoxide intermediate and that the CL was monitoring the concentrations of the epoxide intermediate formed. In order to study drug oxidation and/or activation by reactive oxygen, model enzyme systems capable of generating reactive and oxidizing states of oxygen have been utilized. Using a model system consisting of horseradish peroxidase (HRP) and H202, Misra and Mitchell [21] and Deutsch et al. [22] have observed that addition of morphine results in an activation and irreversible binding of morphine to macromolecules (protein). This interaction has been demonstrated to proceed through a free radical intermediate. Borg [23] has shown that imipramine also forms a free radical when added to the HRP-H20: system but not H202 alone. Similarly, benzo[a]pyrene (BP) is activated to a form which can bind to DNA when added to this model system [24]. BP has also been shown to undergo oxygenation when added to the microsomal fraction of sheep seminal vesicle glands incubated with arachidonic acid [25]. This cooxygenation of BP is believed to arise via an interaction of the microsomal system with hydroperoxide intermediates of prostaglandin synthesis. Both a peroxidase and singlet oxygen have been proposed to be involved in prostaglandin biosynthesis [26,27]. Sivarajah et al. [27] have

78

demonstrated that BP becomes covalently linked to macromolecules during the formation of prostaglandins in guinea pig lung. Both the HRP-H202 system and the sheep microsomal vesicular arachadonic acid system represent univalent oxidizing systems capable not only of generating reactive oxygen but also electronic excitation states as demonstrated by the generation of C L [28,29]. Polymorphonuclear leukocytes have several features in c o m m o n with both of these model systems. These include: (a) the ability to generate both reactive and electronicallyexcited states of oxygen; (b) the involvement of a peroxidase (MPO) in these processes; (c) the capability to oxidize organic molecules. It m a y be possible then to use PMNs, both resing and metabolically activated, as a cellular system to provide the reactive forms of oxygen needed to investigate possible xenobio~c interactionswith reactive oxygen. By using metabolically activated PMNs, a situation where increased reactive oxygen levelsare being produced, it m a y be possible to amplify this interaction. Indeed, this has been demonstrated by the reactive oxygen-mediated binding of estradiol to P M N s and the chemiluminescence response of luminol and indole analogs [8,9,30]. Similarly, the zymosan-induced C L is a standard by which to compare such an amplification. In this report we have provided evidence that other compounds are also capable of interacting with the reactive oxygen provided by P M N s as indicated by the generation of chemiluminescence. These compounds are the heterocyclic N-containing tricyclicantidepressants imipramine, desipramine, opipramol, iprindole and IPNO. Of these compounds, IPNO was the only one which did not yield C L with resting cells although iprindole was the least reactive with both resting and metabolically activated cells.Except for IPNO, the other compounds which failed to yield C L with restingcellsalso failed with zymosan-activated PMNs; in fact these compounds inhibited the C L response brought about by zymosan. The inhibition of the zymosan-initiated C L by amitriptyline and similar tricyclics and chlorimipramine m a y be due to a scavenging of the reactive oxygen. If so, this implies that those compounds which did not yield a CL response with resting cells may also be capable of interacting with reactive oxygen but do not undergo the reaction which results in chemiluminescence. The reaction which results in CL from the drug-cell interaction appears to be related to some aspect of the ring portion of the molecule. This is demonstrated by the activity of iprindole and chlorimipramine which have an aliphatic side chain identical to imipramine but modified ring moieties (Fig. 3 and Table I). However, except for the carbon at position 5 the ring component of amitriptyline is the same as imipramine, yet it did not yield enhanced CL when added to stimulated cells while IPNO, whose ring moiety is identical to imipramine, yielded enhanced CL with particle-activated cells. In addition to differing in the atom at position 5, oxidative metabolism of the ring moiety of imipramine and amitriptyline are somewhat different. Aromatic hydroxylation at position 2 is a major metabolic pathway for imipramine while aliphatic hydroxylation at position 10 is a minor pathway

79

[31]. In contrast, aliphatic hydroxylation at the 10-11 position is a major metabolic pathway for amitriptyline and protriptyline [32]. This aromatic hydroxylation of imipmmine has been proposed to involve an epoxidation step leading to arene oxide formation [33]. Arene oxide formation and associated covalent binding by xenobiotics have been associated with the reactions of tissue necrosis, mutagenesis and carcinogenesis [34]. Intersi> ingly, imipramine has been shown to both covalently bind to liver microsomes and produce necrosis of the liver [35,36]. An epoxide intermediate has been PrOPosed to be involved in these reactions. In summary, the differences in C L between tricyclics seems to be determined by a reaction related to the ring moiety of the molecule. At present, the nature of this reaction is unknown; however, the difference in the ability of tricyclics to undergo arene oxide formation is a possible reaction which could account for the opposite C L responses of compounds so similar in structure, like imipramine and amitriptyline. While further investigations are required to determine the fate of imipramine following interaction wi'th reactive oxygen, the observations reported here are suggestive that h u m a n P M N s may be further utilized as a cellular system to study the interaction of drugs with reactive oxygen. ACKNOWLEDGEMENTS'

The authors are grateful to the staff of the West Virginia University Hospital Outpatient Laboratory for assistance in drawing blood. This research was supported by a West Virginia University Senate Grant and a Pharmaceutical Manufacturers Association Research Starter Grant. REFERENCES 1 G.A. Hamilton, Chemical models and mechanisms for oxygenases, in: O.Hayarshi (Ed.), Molecular Mechanisms of Oxygen Activation, Academic Press, New York, 1974, pp. 405--451. 2 R.C. Allen, R.L. Stjernholm and R.H. Steele, Evidence for the generation of an electronic excitation state(s) in human polymorphonuclear leukocytes and its participation in bactericidal activity, Biochem. Biophys. Res. Commun., 47 (1972) 679. 3 B.D. Cheson, R.L. Chistensen, R. Sperling, B.E. Kohler and B.M. Babior, The origin of the chemiluminescence of phagocytosing granulocytes, J. Clin. Invest., 58 (1976) 789. 4 H. Rosen and S.J. Klebanoff, Chemiluminescence and superoxide production by myeloperoxidase-deficient leukocytes, J. Clin. Invest., 58 (1976) 50. 5 R.L. Stjernholm, R.C. Allen, R.H. Steele, W.W. Waring and J.A. Harris, Impaired chemiluminescence during phagocytosis of opsonized bacteria. Infect. Immun., 7 (1973)713. 6 H. Rosen and S.J. Klebanoff, Formation of singlet oxygen by the myleoperoxidasemediated antimicrobial system, J. Biol. Chem., 252 (1977)4803. 7 K. Fong, T. Noguchi, E.K. Lai, J.M. Heim and P.B. McCay, Inhibition of bacterial killing and of apparent 10~ production by leukocytes with excess supplementation of vitamin E to rats, Fed. Proc., 37 (1978) 707. 8 R.C. Allen and L.D. Loose, Phagocytic activation of a luminol-dependent chemi-

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9 10 11 12 13 14 15 16 17 18 19

20 21 22 23 24 25 26 27 28 29

luminescence in rabbit and peritoneal macrophages, Biochem. Biophys. Res. Commun., 69 (1976) 245. S.J. Klebanoff, Estrogen binding by leukocytes during phagocytosis, J. Exp. Med., 145 (1977) 983. M.A. Trush, K. Van Dyke, M.E. Wilson and M.J. Reasor, Chemiluminescence resulting from an interaction between imipramine and human polymorphonuclear leukocytes, Res. Commun. Chem. Pathol. Pharmacol., 18 (1977) 645. M.A. Trush, M.J. Reasor, M.E. Wilson and K. Van Dyke, Cellular and chemical factors which influence the chemiluminescence resulting from an interaction between imipramine and phagocytic cells, in preparation. M.A. Trush, M.E. Wilson and K. Van Dyke, Generation of electronic excited states (EES) by tricyclic antidepressants: molecular aspects, The Pharmacologist, 19 (1977) 163. M.A. Trush, M.E. Wilson and K. Van Dyke, The generation of chemiluminescence by phagocytic cells, in: M. DeLuca (Ed.), Bioluminescence and Chemiluminescence, Methods in Enzymology, Vol. 57, Academic Press, New York, 1978, pp. 462--494. G.W. Snedecor and W.G. Cochran, Statistical Methods, The Iowa State University Press, Ames, Iowa, 1972. M.H. Bickel and P.L. Gignon, Intracellular binding and metabolism of imipramine and imipramine N-oxide, Chem.-BioL Interactions, 3 (1971) 245. S.D. Nelson, J.R. Mitchell, E. Dybing and H.A. Sasame, Cytochrome P-450-mediated oxidation of 2-hydroxyestrogens to reactive intermediates, Bioehem. Biophys. Res. Commun., 70 (1976) 1157. E. Dybing, S.D. Nelson, J.R. Mitchell, H.A. Sasame and J.R. Gillette, Oxidation of a-methyldopa and other catechols by cytochrome P-450-generated superoxide anion: Possible mechanism of methyldopa hepatitis, Mol. Pharmacol., 12 (1976) 911. J.R. Totter, E.C. De Dugros and C. Riveiro, The use of chemiluminescent compounds as possible indicators of radical production during xanthine oxidase action, J. Biol. Chem., 235 (1960)1839. R.E. Heikkila and F.S. Cabhat, Chemiluminescence from 6-hydroxydopamine: Involvement of hydrogen peroxide, the superoxide radical and the hydroxyl radical, a potential role for singlet oxygen, Res. Commun. Chem. Pathol. Pharmacol., 17 (1977) 649. J.P. Hamman and H.H. Seliger, The chemical formation of excited States during hydroxylation of the carcinogenic hydrocarbon benzo[a]pyrene by rat liver microsomes, Biochem. Biophys. Res. Commun., 70 (1976) 675. A.L. Misra and C.L. Mitchell; Metal ion-catalyzed interaction of peroxidase with morphine and protein, Experientia, 27 (1971) 1442. M.J. Deutsch, R . L . Roerig and R.I.H. Wange, Peroxidase~atalyzed irreversible binding of morphine to protein, Biochem. PharmacoL, 26 (1977) 1267. D.C. Borg, Free radicals from imipramine, Biochem. Pharmacol., 14 (1965) 115. E. Rogan, P. Katomski, R. Roth and E. Cavalieri, Binding of benzo(a)pyrene and 3-methylcholanthrene to DNA by horseradish peroxidase, Fed. Proc., 37 (1978) 750. L.J. Marnett, P. Wlodawer and B. Sameulsson, Co-oxygenation of organic substrates by the prostaglandin synthetase of sheep vesicular gland, J. Biol. Chem., 250 (1975) 8510. P.J. O'Brien and A. Rahimtula, The possible involvement of a peroxidase in prostaglandin biosynthesis, Biochem. Biophys. Res. Commun., 70 (1976) 832. A. Rahimtula and P.J. O'Brien, The possible involvement of singlet oxygen in prostaglandin biosynthesis, Biochem. Biophys. Res. Commun., 70 (1976) 893. K. Sivarajah, M.W. Anderson and T.E. Eling, ~Metabolism of benzo(a)pyrene to reactive intermediates via prostaglandin biosynthesis, Life Sci., 23 (1978) 2571. R.D. Nelson, M.H. Herron, J.R. Schmidtke and R.L. Simmons, Chemiluminescence response of human leukocytes: influence of medium components on light production, Infect. Immun., 17 (1977) 513.

81 30 L.J. Mamett, P. Wlodawer and B. Samuelsson, Light emission during the action of prostaglandin synthetase. Biochem. Biophys. Res. Commun., 60 (1974) 1286. 31 Y. Ushijima, M. Nakamo, Y. Tsuji and H. Inaba, Excitation of indole analogs by phagocytosing leukocytes, Biochem. Biophys. Res. Commun., 82 (1978) 853. 32 M.H. Bickel, Imipramine series, in: E. Usdin and I.S. Forrest (Eds.), Psychotherapeutic Drugs, Part 2 Applications, Marcel Dekker, New York, 1977, pp. 1131--1172. 33 A. Frigerio and C. Pantarotto, Epoxide-diol pathway in the metabolism of tricyclic drugs, J. Pharm. Pharmacol., 29 (1976) 665. 34 J.M. Perel, Pharmacokinetics of therapeutic and toxic reactions: II, Tricyclic Antidepressants, in: H. Rolzin, B. Shiraki and N. Grevic (Eds.), Neurotoxicology, Raven Press, New York, 1977, pp. 157--161. 35 D.M. Jerina and J.W. Daly, Arene oxides: a new aspect of drug metabolism, Science, 185 (1974) 573. 36 H. Kappus and H. Remmer, Irreversible protein binding of ['4C]imipramine with rat and human liver microsomes, Biochem. Pharmacol., 24 (1975) 1079. 37 W.J. Powell, J. Koch-Weser and R.A. Williams, Lethal hepatic necrosis after therapy with imipramine and desipramine, J. Am. Med. Assoc., 206 (1968) 642.

Comparison of the interaction of tricyclic antidepressants with human polymorphonuclear leukocytes as monitored by the generation of chemiluminescence.

Chem.-Biol. Interactions, 28 (1979) 71--81 © Elsevier/North-Holland Scientific Publishers Ltd. 71 COMPARISON OF THE INTERACTION OF TRICYCLIC ANTIDEP...
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