Reduction of toxic metabolite formation of acetaminophen

Biochemical and Biophysical Research Communications 291, 1089 –1094 (2002)
doi:10.1006/bbrc.2002.6541, available online at on Reduction of Toxic Metabolite Formationof Acetaminophen Eszter Hazai, La´szlo´ Vereczkey, and Katalin Monostory1Chemical Research Center, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary diphosphoglucuronic acid and 3Ј-phosphoadenosine-5Ј- Acetaminophen is a widely used over-the-counter
drug that causes severe hepatic damage upon over-
water-soluble conjugates (4). About 3% of ingested dose. Cytochrome P450-dependent oxidation of acet-
acetaminophen is bioactivated by cytochrome P450 en- aminophen results in the formation of the toxic
zymes (CYP1A2, CYP2A6, CYP2E1 and CYP3A4 (4)).
N-acetyl-p-benzoquinone-imine (NAPQI). Inhibition of
Cytochrome P450-dependent oxidation results in the cytochrome P450 enzymes responsible for NAPQI for-
formation of the nontoxic 3-hydroxy-acetaminophen mation might be useful— besides N-acetylcysteine
and the highly reactive N-acetyl-pbenzoquinone-imine treatment—in managing acetaminophen overdose. In-
(NAPQI). NAPQI, which is formed only in a trace vestigations were carried out using human liver mi-
amount upon intake of therapeutic doses, can be de- crosomes to test whether selective inhibition of cyto-
toxified by conjugation with glutathione (Fig. 1). Upon chrome P450s reduces NAPQI formation. Selective
intake of an overdose, the capacity of the organism—to inhibition of CYP3A4 and CYP1A2 did not reduce,
cope with acetaminophen— overloads (the cofactors of whereas the inhibition of CYP2A6 and CYP2E1 signif-
conjugation enzymes as well as glutathione are de- icantly decreased NAPQI formation. Furthermore, se-
pleted) (5). The toxic effect of an overdose results in lective CYP2E1 inhibitors that are used in human
covalent modification of proteins as well as impairment therapy were tested for their inhibitory effect on
of cellular capacity to keep essential thiol groups in NAPQI formation. 4-Methylpyrazole, disulfiram, and
diethyl-dithiocarbamate were the most potent inhibi-
tors with IC

values of 50 M, 8 M, and 33 M, re-
Inhibition of cytochrome P450 enzyme(s) responsible spectively. Although cimetidin is used in the therapy
for the formation of NAPQI might be one of the useful of acetaminophen overdose as an inhibitor of cy-
tools besides N-acetylcysteine treatment in managing tochrome P450, it is not able to reduce NAPQI
acetaminophen overdose. In this way the organism formation.
may gain time to produce cofactors that are necessary 2002 Elsevier Science (USA)
Key Words: acetaminophen; N-acetyl-p-benzoqui-
for the detoxifying pathways. Although in manage- none-imine;
ment strategy of acetaminophen poisoning cimetidine ylpyrazole; disulfiram; diethyl-dithiocarbamate; hu-
is often used as a cytochrome P450-inhibitor to reduce man microsomes; cimetidine.
NAPQI formation, its efficacy is rather questionable (6,7). The aim of our investigation was i) to determine theenzymes responsible for NAPQI formation at lower andhigher doses; ii) to test whether cimetidine efficiently Acetaminophen is one of the most widely used over- inhibits NAPQI formation; iii) to inhibit the formation the-counter drugs with analgesic and antipyretic prop- of NAPQI by using selective cytochrome P450 enzyme erties. Although regarded to be safe at therapeutic doses, acetaminophen is known to cause acute hepaticcentrilobular necrosis in humans when consumed in large doses (1, 2). Acetaminophen overdose results inmore calls to poison centers in the United States than 14C-acetaminophen labelled on the methyl group was overdose with any other pharmacologic substance (3).
synthetized at Chemical Research Center of the Hungarian Academy In biotransformation reactions in human about 90% of of Sciences (Budapest, Hungary). The synthesis was carried out asfollows: 14C-acetic acid was reacted with N-hydroxy-succinimide. The ingested acetaminophen is linked with uridine-5Ј- product was reacted with p-aminophenol. After purification proce-dures, the specific activity of the endproduct was 1.95*1012 Bq ⅐ molϪ1. N-acetyl-p-benzoquinone-imine standard was purchased ϩ36013257548. E-mail: [email protected].
from Sigma (Deisenhofen, Germany). D-Glucose-6-phosphate and 0006-291X/02 $35.00 2002 Elsevier Science (USA)All rights reserved.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS acetaminophen. The incubation mixture contained 5 mg human livermicrosomal protein, selected concentrations of 14C-acetaminophen,10 mM glutathione in 0.1 M Tris-HCl buffer (pH 7.4). The reactionwas initiated by the addition of NADPH-generating system (1 mMNADPH, 5 mM MgCl2, 10 mM glucose-6-phosphate and 2 units/ml ofglucose-6-phosphate dehydrogenase). The final incubation volumewas 500 ␮l. The assay was conducted at 37°C for 40 min, and wasterminated by the addition of 50 ␮l 33% sulfosalicilic acid. NAPQIformation was linear up to 50 min. The mixture was centrifuged thenthe pH of the supernatant was adjusted to 5.0 (by the addition of 2NNaOH) and the sample was analyzed for the formation of NAPQI.
Since NAPQI is a highly reactive molecule, it also binds to proteinspresent in the incubation mixture, which makes the detection ofNAPQI impossible. Therefore, NAPQI was detected as its glutathi-one conjugate, 3-(glutathione-S-yl)acetaminophen (GS-acetamino-phen). GS-acetaminophen is immediately formed in the presence ofreduced glutathione and NAPQI (14).
The incubation process was the same as de- scribed above. Acetaminophen was used at 0.25 mM concentration.
The following specific cytochrome P450 enzyme inhibitors were used:␣-naphtoflavone (100 ␮M, for CYP1A2), 8-methoxypsoralen (10 ␮M,for CYP2A6), diethyl-dithiocarbamate (100 ␮M, for CYP2E1), trole-andomycin (200 ␮M, for CYP3A4). The following published cyto-chrome P450 inhibitors at 100 ␮M concentration were tested forNAPQI production: cimetidine, chlorpromazine, diclofenac, fluphen-azine, thioridazine, isoniazid, diallyl sulfide, 4-methyl pyrazole, di-sulfiram.
A new chromatographic method has been de- veloped in our laboratory for the detection of GS-acetaminophen.
Compounds were separated on a Merck Lichrospher RP-18 column 5␮m (250 mm*4 mm) column (Darmstadt, Germany), protected by acartridge guard column (30*4 mm) packed with identical solid phase.
The mobile phase consisted of 40 mM NH4-acetate (pH ϭ 4.8):methanol ϭ 87:13 (v/v) at a flow rate of 1 mL ⅐ minϪ1. The compoundswere detected both by their UV absorption at 250 nm and accordingto 14C activity.
conjugate and selective cytochrome P450 enzyme activities (phenac-etin O-deethylation of CYP1A2, coumarin 7-hydroxylation of Cytochrome P450-dependent metabolism of acetamino- CYP2A6, chlorzoxazone 6-hydroxylation of CYP2E1, nifedipine oxi- dation of CYP3A4) for each preparation of liver microsomes werecompared by simple linear regression analysis for each pair of data.
D-glucose-6-phosphate dehydrogenase (E.C. were obtainedfrom Calbiochem (La Jolla, CA, USA). 5-Sulfosalicylic acid, reduced glutathione and methanol of HPLC grade were obtained from Merck(Darmstadt, Germany). All other chemicals were from Reanal(Budapest, Hungary).
Correlation of NAPQI formation and specific enzyme Preparation of human liver microsomes. kidney transplant donors were from Transplantation and Surgery nors were characterized with substrates selective for Clinic of Semmelweis University (Budapest, Hungary). Permission different cytochrome P450s that are responsible for the of Local Research Ethics Committee was obtained for the use of oxidative metabolism of majority of drugs. Results of human liver tissues. Samples of human liver microsomes were pre- pared as described in (8). Microsomal protein concentration was The formation of NAPQI (assayed as its glutathione determined by the method of Lowry (9), with bovine serum albuminas standard.
conjugate, 3-(glutathione-S-yl)acetaminophen, GS-acet-aminophen) was investigated i) at low (0.05 mM) and termine specific enzyme activities of CYP1A2 (10), CYP2A6 (11), ii) at high (0.25 mM) acetaminophen concentrations CYP2E1 (12) and CYP3A4 (13). The incubation mixtures contained (Table 1). The structure of GS-acetaminophen was human liver microsomal protein, a NADPH-generating system (1 also confirmed by LC/MS study with authentic stan- mM NADPH, 10 mM glucose 6-phosphate, 5 mM MgCl2 and 2 dard (Hazai et al., 2001 submitted for publication in units/ml glucose 6-phosphate dehydrogenase); and various selective substrates for cytochrome P450 forms (0.2 mM phenacetin forCYP1A2, 0.2 mM coumarin for CYP2A6, 0.5 mM chlorzoxazone for At lower acetaminophen concentration no correla- CYP2E1, 0.2 mM nifedipine for CYP3A4).
tion was found between NAPQI formation and the spe- Biotransformation of acetaminophen. cific cytochrome P450 activities (CYP1A2, CYP2A6, NAPQI were identified at 0.05 mM and 0.25 mM concentrations of CYP2E1 and CYP3A4 activities) (Table 1). At 0.25 mM BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Characterization of Human Liver Microsomes (HHM) for Selective Substrates of Cytochrome P450 Enzymes (Phenacetin O-Deethylation of CYP1A2, Coumarin 7-Hydroxylation of CYP2A6, Chlorzoxazone 6-Hydroxylation of CYP2E1, NifedipineOxidation of CYP3A4), and for the Formation of GS-Acetaminophen Conjugate at Different Acetaminophen Concentrations Note. The values are expressed as pmol product/(mg microsomal protein*min). The correlation of the production of GS-acetaminophen conjugate and selective cytochrome P450 enzyme activities are presented. Each pair of data was compared by simple linear regression. R2values of the linear regression analysis are presented for each specific enzyme activities at two acetaminophen concentrations.
concentration there was a marked correlation (with an further evidence for the participation of cytochrome R2 value of 0.9381) between the formation of NAPQI P450 forms in the formation of NAPQI. Selective inhi- and the specific enzyme activity of CYP2E1 (Table 1, bition of CYP3A4 and CYP1A2 did not reduce the Fig. 2). However, no correlation was found between the amount of NAPQI, whereas the inhibition of CYP2A6 formation of NAPQI and other specific cytochrome and CYP2E1 resulted in a marked decrease of NAPQI P450 enzyme activities (CYP1A2, CYP2A6, and Furthermore, it has been studied if known CYP2E1 and CYP2A6 inhibitors, which can be administered to bition studies were also carried out in order to provide humans, are able to reduce the formation of NAPQI at0.25 mM acetaminophen concentration. The followinginhibitors of CYP2E1 and/or CYP2A6 were subject toour investigation: chlorpromazine, diclofenac, fluphen-azine, thioridazine, isoniazid, diallyl sulfide, 4-methylpyrazole, disulfiram and its metabolite, diethyl-dithiocarbamate.
carbamate (at 100 ␮M concentration) reduced NAPQIformation to 7 Ϯ 1% and 23 Ϯ 13%, respectively (Fig.
4). 4-Methyl pyrazole (at 100 ␮M concentration) de-creased NAPQI formation to 35 Ϯ 1%. Isoniazid anddiallyl sulfide showed a modest inhibitory effect on theformation of NAPQI (to 74 Ϯ 5% and 45 Ϯ 2%, respec-tively) (Fig. 4). The use of 100 ␮M cimetidine, chlor-promazine, diclofenac, fluphenazine and thioridazinedid not reduce the formation of NAPQI (Fig. 4). How-ever, these substances listed above were considered tobe CYP2E1 inhibitors (15).
The inhibitory effect at different inhibitor concentra- tions was studied with the most potent inhibitors in Formation of NAPQI as the function of CYP2E1 activity at 0.25 mM acetaminophen concentration. HHM means samples of human microsomes. Specific CYP2E1 enzyme activity was measured ␮M for disulfiram, 33 ␮M for diethyl-dithio- with chlorzoxazone 6-hydroxylase reaction.
carbamate and 50 ␮M for 4-methyl pyrazole (Fig. 5).
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Formation of NAPQI in the presence of specific cytochrome P450 inhibitors. Control means the microsomal activity in the absence of inhibitors. The following specific inhibitors were used: troleandomycin (200 ␮M, CYP3A4); ␣-naphtoflavone (100 ␮M, CYP1A2);8-methoxypsoralen (10 ␮M, CYP2A6) diethyl-dithiocarbamate (100 ␮M, CYP2E1).
There are controversial reports on the role of differ- Several forms of cytochrome P450 in humans, in- CYP2E1, CYP3A4) in NAPQI formation at higher dose.
cluding 1A2, 2A6, 2E1, 3A4 have been shown to cata- All of the cytochrome P450 forms listed above have lyze the oxidation of acetaminophen to NAPQI (5).
been reported to contribute significantly to acetamino- CYP3A4 was suggested to play an appreciable role at phen toxicity (5, 17–19). However, studies using lower doses (16). Our study demonstrated that at low CYP1A2 null mice did not confirm the role of CYP1A2 concentration there is no enzyme primarily responsible in acetaminophen toxicity (20). Our correlation study confirmed the role of CYP2E1 in NAPQI formation at The effect of cytochrome P450 inhibitors on the formation of NAPQI. All inhibitors were used at 100 ␮M concentration.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS patients, methanol and ethylene-glycol poisoning (Fo-mepiazole), can be administered intravenously as well(26, 27). The other potent inhibitor, disulfiram (Antetil,Antabuse) is used in the therapy of alcoholic patientsas alcohol-dehydrogenase inhibitor. This compound isalso a known specific CYP2E1 inhibitor (28, 29). Thefirst step in the biotransformation of disulfiram is thethiol-dependent reduction to two molecules of diethyl-dithiocarbamate (30). Diethyl-dithiocarbamate is aknown inhibitor of both enzymes (CYP2E1, CYP2A6)(21) that are responsible for the formation of NAPQI.
According to our present knowledge it does not inhibitany other known cytochrome P450 enzymes. This sub-stance is, however, not yet used in human therapy.
Isoniazid also showed inhibitory effect toward NAPQI formation. However, it is not only an inhibitorbut also acts as an inducer for CYP2E1. The mecha-nism of induction is the stabilization of the enzymeprotein (31, 32). There has been a case report, where Formation of NAPQI in the presence of various concen- the administration of isoniazid potentiated the toxic trations of 4-methyl pyrazole, diethyl-dithiocarbamate, and disul- effect of acetaminophen (33). The toxicity might be due to the induction of CYP2E1 as a consequence of isoni-azid administration. Therefore, the use of isoniazid higher concentration. 0.25 mM acetaminophen concen- seems to be disadvantageous in the case of acetamin- tration is consistent with a toxic dose of acetaminophen ophen poisoning. Diallyl-sulfide, a component of garlic as can be concluded from the Rumack-Mathew nomo- has also shown a modest inhibitory effect. However, gram (6). On the other hand, as the inhibition studies this substance is not used in the clinical practice.
revealed, CYP2A6 also participated in NAPQI forma- The dose dependence of the inhibitory effect was also tion. Considering the results of correlation and specific studied in the case of three potent inhibitors (4- inhibition studies and the fact that CYP2E1 is 6.9 Ϯ methylpyrazole, disulfiram, diethyl-dithiocarbamate) 2.9% and CYP2A6 is 4.0 Ϯ 3.2% of total cytochrome (Fig. 5). It can be concluded that 100 ␮M concentration P450 in human liver (21), it can be concluded that of the inhibitor is required in order to achieve the these two enzymes are mainly responsible for the for- maximal inhibitory effect. The further, fivefold in- mation of NAPQI at higher concentration. Further- crease of the amount of inhibitor is unnecessary, since more, our results suggest that CYP1A2 and CYP3A4 it does not improve its inhibitory effect.
do not contribute significantly to NAPQI formation at Finally, it should be concluded that at lower dose higher acetaminophen concentration. This finding is several enzymes participate in the formation of consistent with the studies of bacolovirus-expressed NAPQI. In overdose conditions CYP2E1 and CYP2A6 and purified human liver microsomes, where CYP2A6 are mainly responsible for the toxic effect of acetamin- and CYP2E1 were suggested to play a major role in ophen. Cimetidine does not play a role in inhibiting the formation of NAPQI as both in vitro and in vivo human Cimetidine showed no inhibitory effect toward studies revealed. Therefore, the use of this substance is NAPQI formation. According to some authors, cimeti- not suggested in the case of acetaminophen poisoning.
dine is useful in the treatment of acetaminophen over- Disulfiram is the most potent inhibitor of NAPQI for- dose because of its cytochrome P450 inhibitory effect mation in human liver microsomes. 4-Methylpyrazole, (22, 23). However, cimetidine inhibits CYP2C9 enzyme which can also be administered intravenously, might (24), which is not involved in the metabolism of acet- also be a useful tool in managing acetaminophen over- aminophen. The fact that cimetidine is not useful in managing acetaminophen overdose has also beenproved in clinical investigations (6, 25). Therefore, al- though in some countries suggested, the administra-tion of cimetidine seems to be ineffective in the case of 1. Vermeulen, N. P., Bessems, J. G., and Van de Straat, R. (1992) Molecular aspects of paracetamol-induced hepatotoxicity and itsmechanism-based prevention. Drug Metab. Rev. (United States) 4-Methylpyrazole, disulfiram and diethyl-dihthio- 24, 367– 407.
carbamate significantly reduced NAPQI formation.
2. Prescott, L. F. (1996) Paracetamol (Acetaminophen) a Critical Among these substances 4-methylpyrazole, which is Bibliographic Review, pp. 285–351, Taylor & Francis Ltd., Lon- used in human therapy in the treatment of alcoholic BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 3. Litovitz, T. L., Klein-Schwartz, W., Dyer, K. S., Shannon, M., Guengerich, F. P., and Yang, C. S. (1993) Cytochrome P450 Lee, S., and Powers, M. (1998) 1997 annual report of the Amer- enzymes involved in acetaminophen activation by rat and hu- ican Association of Poison Control Centers Toxic Exposure Sur- man liver microsomes and their kinetics. Chem. Res. Toxicol. veillance System. Am. J. Emerg. Med. (United States) 16, 443–
(United States) 6, 511–518.
19. Thummel, K. E., Lee, C. A., Kunze, K. L., Nelson, S. D., and 4. Bessems, J. (2000) Hepatotoxicity of Paracetamol and Structural Slattery, J. T. (1993) Oxidation of acetaminophen to N-acetyl-p- Analogues, Thesis Vrije Universiteit Amsterdam.
aminobenzoquinone imine by human CYP3A4. Biochem. Phar- 5. Chen, W., Koenigs, L. L., Thompson, S. J., Raimund, M. P., macol. (England) 45, 1563–1569.
Rettie, A. E., Trager, W. F., and Nelson, S. D. (1998) Oxidation of 20. Tonge, R. P., Kelly, E. J., Bruschi, S. A., Kalhorn, T., Eaton, acetaminophen to its toxic quinone metabolite and nontoxic cat- D. L., Nebert, D. W., and Nelson, S. D. (1998) Role of CYP1A2 in echol metabolites by bacolovirus-expressed and human purified the hepatotoxicity of acetaminophen: Investigations using cytochromes P4502E1 and P4502A6. Chem. Res. Toxicol. 11,
Cyp1a2 null mice. Toxicol. Appl. Pharmacol. (United States) 153,
6. Zed, P. J., and Krenzelok, E. P. (1999) Treatment of acetamino- 21. Ioannides, C. (1996) Cytochromes P450 Metabolic and Toxicolog- phen overdose. Am. J. Health-Syst. Pharm. 56, 1081–1093.
ical Aspects, CRC Press Inc., Boca Raton.
7. Knodell, R. G., Browne, D. G., Gwozdz, G. P., Brian, W. R., and 22. Al-Mustafa, Z. H., Al-Ali, A. K., Qaw, F. S., and Abdul-Cader, Z.
Guengerich, F. P. (1991) Differential inhibition of individual (1997) Cimetidine enhances the hepatoprotective action of human liver cytochromes P-450 by cimetidine. Gastroenterology N-acetylcysteine in mice treated with toxic doses of paracetamol.
(United States) 101, 1680 –1691.
Toxicology (Ireland) 121, 223–228.
8. Van der Hoeven, T. A., and Coon, N. J. K. (1974) Preparation and 23. Garba, M., Odunola, M. T., and Ahmed, B. H. (1999) Effect of properties of partially purified cytochrome P-450 and reduced study protocol on the interactions between cimetidine and parac- nicotinamide adenine dinucleotide phosphate-cytochrome P-450 etamol in man. Eur. J. Drug Metab. Pharmacokinet. (Switzer- reductase from rabbit liver microsomes. J. Biol. Chem. 249,
land) 24, 159 –162.
24. Pichard, L., Fabre, I., Fabre, G., Domergue, J., Aubert, B. S., 9. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J.
Mourad, G., and Maurel, P. (1990) Screening for inducers and (1951) Protein measurement with Folin reagent. J. Biol. Chem. inhibitors of cytochrome P-450 in primary cultures of human 193, 265–275.
hepatocytes and in human liver microsomes. Drug Metab. Disp. 10. Butler, M. A., Iwasaki, M., Guengerich, F. P., and Kadlubar, 18, 595– 606.
F. F. (1989) Human cytochrome P-450PA (P-450IA2), the 25. Burkhart, K. K., Janco, N., and Kulig, K. W. (1995) Cimetidine phenacetin-O-deethylase, is primary responsible for the hepatic as adjunctive treatment for acetaminophen overdose. Hum. Exp. 3-demethylation of caffeine and N-oxidation of carcinogenic Toxicol. 14, 299 –304.
arylamines. Proc. Natl. Acad. Sci. USA 86, 7696 –7700.
26. Hantson, P., Hassoun, A., and Mahieu, P. (1998) Ethylene glycol 11. Raunio, H., Syngelma, T., Pasanen, M., Juvonen, R., Honkakosi, poisoning treated by intravenous 4-methylpyrazole. Intensive P., Kairaluoma, M. A., Sotaniemei, E., Lang, M. A., and Care Med. 24, 736 –739.
Pelkonen, O. (1988) Immunochemical and catalytical studies on 27. Dawidek-Pietryka, K., Szczepaniak, S., Dudka, J., and Mazur, hepatic coumarin-7-hydroxylase in man, rat and mouse. Bio- M. (1998) In vitro studies of human alcohol dehydrogenase inhi- chem. Pharmacol. 37, 3889 –3895.
bition in the process of methanol and ethylene glycol oxidation.
12. Peter, R., Bocker, R., Beaune, O. H., Iwasaki, M., Guengerich, Arch. Toxicol. 72, 604 – 607.
F. P., and Yang, C. S. (1990) Hydroxylation of chlorzoxazone as 28. Emery, M. G., Jubert, C., Thummel, K. E., and Kharasch, E. D.
a specific probe for human liver cytochrome P-450IIE1. Chem. (1999) Duration of cytochrome P-450 2E1 (CYP2E1) inhibition Res. Toxicol. 5, 54 –59.
and estimation of functional CYP2E1 enzyme half-life after 13. Guengerich, F. P., Martin, V. M., Beaune, P. H., Kremers, P., single-dose disulfiram administration in humans. J. Pharmacol. Wolff, T., and Waxman, D. J. (1986) Characterization of rat and Exp. Ther. 291, 213–219.
human liver microsomal cytochrome P-450 forms involved in 29. Kharasch, E. D., Hankins, D. C., Jubert, C., Thummel, K. E., and nifedipine oxidation, a prototype for genetic polymorphism in Taraday, J. K. (1999) Lack of single single-dose disulfiram effects oxidative drug metabolism. J. Biol. Chem. 261, 5051–5060.
on cytochrome P-450 2C9, 2C19, 2D5 and 3A4 activities: Evi- 14. Potter, D. W., and Hinson, J. A. (1986) Reactions of N-acetyl-p- dence for specificity toward P-450 2E1. Drug Metab. Disp. 27,
benzoquinone-imine with reduced glutathione, acetaminophen and NADPH. Mol. Pharmacol. 30, 33– 41.
30. Madan, A., Parkinson, A., and Faiman, M. D. (1995) Identifica- 15. Tassaneeyakul, W., Birkett, D. J., and Miners, J. O. (1998) tion of the human and rat P450 enzymes responsible for the Inhibition of human hepatic cytochrome P4502E1 by azole anti- formation of S-methyl N,N diethyldithiocarbamate (DETC-Me).
fungals, CNS-active drugs and non-steroidal anti-inflammatory Drug Metab. Disp. 23, 1153–1162.
agents. Xenobiotica 28, 293–301.
31. Eliasson, E., Johansson, I., and Ingelman-Sundberg, M. (1995) 16. Manyike, P. T., Kharasch, E. D., Kalhorn, T. F., and Slattery, Substrate-, hormone- and cAMP-regulated cytochrome P450 J. T. (2000) Contribution of CYP2E1 and CYP3A to acetamino- degradation. Proc. Natl. Acad. Sci. USA 87, 3225.
phen reactive metabolite formation. Clin. Pharmacol. Ther. 32. Ronis, M. J. J., Lindros, K. O., and Ingelman-Sundberg, M.
(United States) 67, 275–282.
(1996) The CYP2E Subfamily, in Cytochromes P450 Metabolic 17. Raucy, J. L., Lasker, J. M., Lieber, C. S., and Black, M. (1989) and Toxicological Aspects (Ioannides, C., Ed.), pp. 211–240, CRC P450IIE1 and P450IA2. Arch. Biochem. Biophys. (United States) 33. Murphy, R., Swartz, R., and Watkins, P. B. (1990) Severe Acet- 271, 270 –283.
aminophen toxicity in a patient receiving isoniazid. Annals Inter. 18. Patten, C. J., Thomas, P. E., Guy, R. L., Lee, M., Gonzalez, F. J., Med. 113, 799 – 800.


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