Mechanisms of the Formation and Disposition of Reactive Metabolites That can Cause Acute Liver Injury

References

• Miller E. C., Miller J. A. The presence and significance of bound aminazo dyes in the livers of rats fed p-dimethylaminoazo-benzene. Cancer Res. 1947; 7: 468–480
   Web of Science ®Google Scholar
• Recent advances in drug metabolism and toxicity. Semin. Liver Dis., P. D. Berk, C. S. Lieber, F. Schaffner, N. Kaplowitz, 1990; 10: 233–338
   Google Scholar
• Hinson J. A., Pumford N. R., Nelson S. D. The role of metabolic activation in drug toxicity. Drug Metab. Rev. 1994; 26: 395–412
   PubMed Web of Science ®Google Scholar
• Bioactivation of Foreign Compounds, M. W. Anders. Academic Press, Orlando, FL 1985
   Google Scholar
• Monks T. J., Lau S. S. Reactive intermediates and their toxi-cological significance. Toxicology 1988; 52: 1–53
   PubMed Web of Science ®Google Scholar
• Biological Reactive Intermediates IV, C. M. Witmer, R. R. Snyder, D. J. Jollow, G. F. Kalf, J. J. Kocsis, I. G. Sipes. Plenum Press, New York 1991
   Google Scholar
• Guengerich F. P., Shimada T. Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chetn. Res. Toxicol. 1991; 4: 391–407
   PubMed Web of Science ®Google Scholar
• Nelson S. D., Pearson P. G. Covalent and noncovalent interactions in acute lethal cell injury caused by chemicals. Ann. Rev. Pharmacol. Toxicol. 1990; 30: 169–195
   PubMed Web of Science ®Google Scholar
• Hinson J. A., Roberts D. W. Role of covalent and noncovalent interactions in cell toxicity: Effects on proteins. Ann. Rev. Pharmacol. Toxicol. 1992; 32: 471–510
   PubMed Web of Science ®Google Scholar
• Satoh H., Fukuda Y., Anderson D. K., Ferrans V. J., Gillette J. R., Pohl L. R. Immunological studies on the mechanism of halothane-induced hepatotoxicity: Immunochemical evidence of trifluoroacetylated hepatocytes. J. Pharmacol. Exp. Ther. 1985; 233: 857–862
   PubMed Web of Science ®Google Scholar
• Pohl L. R. An immunochemical approach of identifying and characterizing protein targets of toxic reactive metabolites. Chem. Res. Toxicol. 1993; 6: 786–793
   PubMed Web of Science ®Google Scholar
• Hinson J. A. Biochemical toxicology of acetaminophen. Rev. Biochem. Toxicol. 1980; 2: 103–130
   Google Scholar
• Black M. Acetaminophen hepatotoxicity. Ann. Rev. Med. 1984; 35: 577–593
   PubMed Web of Science ®Google Scholar
• Nelson S. D. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin. Liver Dis. 1990; 10: 267–278
   PubMed Web of Science ®Google Scholar
• Vermeulen N. P. E., Bessems J. G. M., van de Straat R. Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention. Drug Metab. Rev. 1992; 24: 367–407
   PubMed Web of Science ®Google Scholar
• Mitchell J. R., Jollow D. J., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Ther. 1973; 187: 185–194
   PubMed Web of Science ®Google Scholar
• Jollow D. J., Mitchell J. R., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. 1973; 187: 195–202
   PubMed Web of Science ®Google Scholar
• Potter W. Z., Davis D. C., Mitchell J. R., Jollow D. J., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vivo. J. Pharmacol. Exp. Ther. 1973; 187: 203–210
   PubMed Web of Science ®Google Scholar
• Mitchell J. R., Jollow D. J., Potter W. Z., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 1973; 187: 211–217
   PubMed Web of Science ®Google Scholar
• Jollow D. J., Thorgeirsson S. S., Potter W. Z., Hashimoto M., Mitchell J. R. Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen. Pharmacology 1974; 12: 251–271
   PubMed Web of Science ®Google Scholar
• Hinson J. A., Pohl L. R., Gillette J. R. N-Hydroxyacetamino-phen: A microsomal metabolite of N-hydroxypenacetin but apparently not acetaminophen. Life Sci. 1979; 24: 2133–2138
   PubMed Web of Science ®Google Scholar
• Nelson S. D., Forte A. J., Dahlin D. C. Lack of evidence for AMiydroxyacetaminophen as a reactive metabolite of acetaminophen in vitro. Biochem. Pharmacol 1980; 29: 1617–1620
   PubMed Web of Science ®Google Scholar
• Miner D. J., Kissinger P. T. Evidence for the involvement of N-acetyl-p-benzoquinone imine in acetaminophen metabolism. Biochem. Pharmacol. 1979; 28: 3285–3290
   PubMed Web of Science ®Google Scholar
• Corcoran G. B., Mitchell J. R., Vaishnav Y. N., Horning E. C. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate. N-acetyl-p-benzoquinone imine, Mol. Pharmacol 1980; 18: 536–542
   PubMed Web of Science ®Google Scholar
• Dahlin D. C., Miwa G. T., Lu A. Y. H., Nelson S. D. N-Acetyl-p-benzoquinone imine: A cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. USA 1984; 81: 1327–1331
   PubMed Web of Science ®Google Scholar
• Harvison P. J., Guengerich G. P., Rashed M. S., Nelson S. D. Cytochrome P-450 isozyme selectivity in the oxidation of acetaminophen. Chem. Res. Toxicol. 1988; 1: 47–52
   PubMed Web of Science ®Google Scholar
• Dahlin D. C., Nelson S. D. Synthesis, decomposition kinetics and preliminary toxicological studies on pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen. J. Med. Chem. 1982; 25: 885–886
   PubMed Web of Science ®Google Scholar
• Holme J. A., Dahlin D. C., Nelson S. D., Dybing E. Cytotoxic effects of N-acetyl-p-benzoquinone imine, a common arylating intermediate of paracetamol and N-hydroxy-paracetamol. Biochem. Pharmacol. 1984; 33: 401–406
   PubMed Web of Science ®Google Scholar
• Blair I. A., Boobis A. R., Davies D. J., Cresp T. M. Paracetamol oxidation: Synthesis and reactivity of iV-acetyl-p-benzo-quinone imine. Tetrahedron Lett. 1980; 21: 4947–4950
   Web of Science ®Google Scholar
• Albano E., Rundgren M., Harvison P. J., Nelson S. D., Moldeus P. Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol. Pharmacol. 1985; 280: 306–311
   Google Scholar
• Morgan E. T., Koop D. R., Coon M. J. Comparisons of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem. Biophys. Res. Commun 1983; 112: 8–13
   PubMed Web of Science ®Google Scholar
• Steele C. M., Masson H. A., Batterskill J. M., Gibson G. G., Ioannides C. Metabolic activation of paracetamol by highly purified forms of cytochrome P-450. Res. Commun. Chem. Pathol. Pharmacol. 1983; 40: 109–119
   PubMedGoogle Scholar
• Raucy J. L., Lasker J. M., Lieber C. S., Black M. Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch. Biochem. Biophys. 1989; 271: 270–283
   PubMed Web of Science ®Google Scholar
• Patten C. J., Thomas P. E., Guy R. L., Lee M., Gonzalez F. J., Guengerich F. P., Yang C. S. Cytochrome P450 Enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem. Res. Toxicol. 1993; 6: 511–518
   PubMed Web of Science ®Google Scholar
• Lee C. A., Thummel K. E., Kalhorn T. F., Nelson S. D., Slattery J. T. Inhibition and activation of acetaminophen-reactive metabolite formation by caffeine: Roles of cytochrome P-450 1A2 and 3A2. Drug Metab. Dispos. 1991; 19: 348–353
   PubMed Web of Science ®Google Scholar
• Thummel K. E., Lee C. A., Kunze K. L., Nelson S. D., Slattery J. T. Oxidation of acetaminophen to N-acetyl-p-aminobenzo-quinone imine by human CYP3A4. Biochem. Pharmacol. 1993; 45: 1563–1569
   PubMed Web of Science ®Google Scholar
• Ryan D. E., Koop D. R., Thomas P. E., Coon M. J., Levin W. Evidence that isoniazid and ethanol induce the same microsomal cytochrome P-450 in rat liver, an isozyme homologous to rabbit liver cytochrome P-450 isozyme 3a. Arch. Biochem. Biophys. 1986; 246: 633–644
   PubMed Web of Science ®Google Scholar
• McClain C. J., Kromhout J. P., Peterson F. J., Holtzman J. L. Potentiation of acetaminophen hepatotoxicity by alcohol. J. Am. Med. Assoc 1980; 244: 251–253
   PubMed Web of Science ®Google Scholar
• Hall A. H., Kulig K. W., Rumack B. H. Acetaminophen hepatotoxicity in alcoholics,. Ann. Intern. Med. 1986; 105: 624
   Web of Science ®Google Scholar
• Seeff L. B., Cuccherini B. A., Zimmerman H. J., Adler E., Benjamin S. B. Acetaminophen hepatotoxicity in alcoholics: A therapeutic misadventure. Ann. Intern. Med. 1986; 104: 399–404
   PubMed Web of Science ®Google Scholar
• Murphy R., Swarz R., Watkins P. B. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann. Intern. Med. 1990; 113: 799–800
   PubMed Web of Science ®Google Scholar
• Zand R., Nelson S. D., Slattery J. T., Thummel K. E., Kalhorn T. F., Adams S. P., Wright J. M. Inhibition and induction of cytochrome P450 2E1-catalyzed oxidation by isoniazid in humans. Clin. Pharm. Ther. 1993; 54: 142–149
   PubMed Web of Science ®Google Scholar
• Nolan C. M., Sandblom R. E., Thummel K. E., Slattery J. T., Nelson S. D. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 1994; 105: 408–411
   PubMed Web of Science ®Google Scholar
• Knox J. H., Jurand J. Determination of paracetamol and its metabolites in urine by high-performance liquid chromatography using reversed-phase bonded supports. J. Chromatogr. 1977; 142: 651–670
   PubMed Web of Science ®Google Scholar
• Hinson J. A., Pohl L. R., Monks T. J., Gillette J. R., Guengerich F. P. 3-Hydroxyacetaminophen: A microsomal metabolite of acetaminophen. Drug Metab. Dispos. 1980; 8: 289–294
   PubMed Web of Science ®Google Scholar
• Forte A. J., Wilson J. M., Slattery J. T., Nelson S. D. The formation and toxicity of catechol metabolites of acetaminophen in mice. Drug Metab. Dispos. 1984; 12: 484–491
   PubMed Web of Science ®Google Scholar
• van de Straat R., de Vries J., de Boer H. J. R., Vromans R. M., Vermeulen N. P. E. Relationship between paracetamol binding to and its oxidation by two cytochrome P450 isozymes—A proton nuclear magnetic resonance and spectrophotometric study. Xenobiotica 1987; 17: 1–9
   PubMed Web of Science ®Google Scholar
• Koymans L., van Lenthe J. H., van de Straat R., Donne-op den Kelder G. M., Vermeulen N. P. E. A theoretical study on the metabolic activation of paracetamol by cytochrome P450: Indications of a uniform mechanism. Chem. Res. Toxicol. 1989; 2: 60–66
   PubMed Web of Science ®Google Scholar
• Hinson J. A., Mitchell J. R. N-Hydroxylation of phenacetin by hamster liver microsomes. Drug Metab. Dispos. 1976; 4: 430–435
   PubMed Web of Science ®Google Scholar
• Astrom A., DePierre J. W. Metabolism of 2-acetylamino-fluorene by eight different forms of cytochrome P450 isolated from liver. Carcinogenesis 1985; 6: 113–120
   PubMed Web of Science ®Google Scholar
• McManus M. E., Burgess W. M., Veronese M. E., Huggett A., Quattrochi L. C., Tukey R. H. Metabolism of 2-acetylamino-fluorene and benzo[a]pyrene and activation of food-derived heterocyclic mutagens by human cytochromes P450. Cancer Res. 1990; 50: 3367–3376
   PubMed Web of Science ®Google Scholar
• Loew G. H., Goldblum A. Metabolic activation and toxicity of acetaminophen and related analogs. Mol. Pharmacol. 1985; 27: 375–386
   PubMed Web of Science ®Google Scholar
• Myers T. G., Thummel K. E., Kalhorn T. F., Nelson S. D. Preferred orientations in the binding of 4′-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and l5N-NMR relaxation studies. J. Med. Chem. 1994; 37: 860–867
   PubMed Web of Science ®Google Scholar
• Guengerich F. P., Macdonald T. L. Chemical mechanisms of catalysis by cytochromes P-450: A unified view. Ace. Chem. Res. 1984; 17: 9–16
   Web of Science ®Google Scholar
• Ortiz de Montellano P. R. Cytochrome P-450 catalysis: Radical intermediates and dehydrogenation reactions. Trends Pharmacol. Sci. 1989; 10: 354–359
   PubMed Web of Science ®Google Scholar
• White R. E. The involvement of free radicals in the mechanisms of monooxygenases. Pharmacol. Ther. 1991; 49: 21–42
   PubMed Web of Science ®Google Scholar
• Baillie T. A., Tirmenstein M. A., Nelson S. D., unpublished results
   Google Scholar
• Raag R., Poulos T. L. Crystal structures of cytochrome P450cam complexed with camphane, thiocamphor, and adamantane: Factors controlling P450 substrate hydroxylation. Biochemistry 1991; 30: 2674–2684
   PubMed Web of Science ®Google Scholar
• Crull G. B., Kennington J. W., Garber A. R., Ellis P. D., Dawson J. H. 19F-Nuclear magnetic resonance as a probe of the spatial relationship between the heme iron of cytochrome P450 and its substrate. J. Biol. Chem. 1989; 264: 2649–2655
   PubMed Web of Science ®Google Scholar
• Streeter A. J., Dahlin D. C., Nelson S. D., Baillie T. A. The covalent binding of acetaminophen to protein: Evidence for cysteine residues as major sites of arylation in vitro. Chem.-Biol. Interact 1984; 48: 349–366
   PubMed Web of Science ®Google Scholar
• Hoffman K.x K.-, Streeter A. J., Axworthy D. B., Baillie T. A. Identification of the major covalent adduct formed in vitro and in vivo between acetaminophen and mouse liver proteins. Mol. Pharmacol. 1985; 27: 566–573
   PubMed Web of Science ®Google Scholar
• Potter D. W., Pumford N. R., Hinson J. A., Benson R. W., Roberts D. W. Epitope characterization of acetaminophen bound to protein and nonprotein sulfhydryl groups by an enzyme-linked immunosorbent assay. J. Pharmacol. Exp. Ther. 1989; 248: 182–189
   PubMed Web of Science ®Google Scholar
• Nelson S. D., Vaishnav Y., Kambara H., Baillie T. A. Comparative EI, CI and FD mass spectra of some thioether metabolites of acetaminophen. Biomed. Mass Spectrum. 1981; 8: 244–251
   Google Scholar
• Hinson J. A., Monks T. J., Hong M., Highet R. J., Pohl L. R. 3-(GIutathion-S-yl)acetaminophen: A biliary metabolite of acetaminophen. Drug Metab. Dispos. 1982; 10: 47–50
   PubMed Web of Science ®Google Scholar
• Rashed M. S., Myers T. G., Nelson S. D. Hepatic protein arylation, glutathione depletion, and metabolite profiles of acetaminophen and a non-hepatotoxic regioisomer, 3′-hydroxyacetanilide, in the mouse. Drug Metab. Dispos. 1990; 18: 765–770
   PubMed Web of Science ®Google Scholar
• Tirmenstein M. A., Nelson S. D. Subcellular binding effects on calcium homeostasis produced by acetaminophen and a non-hepatotoxic regioisomer, 3′-hydroxyacetanilide. J. Biol. Chem. 1989; 264: 9814–9819
   PubMed Web of Science ®Google Scholar
• Roberts S. A., Price V. F., Jollow D. J. Acetaminophen struc-ture-toxicity studies: In vivo covalent binding of a nonhepatotoxic analog, 3-hydroxyacetanilide. Toxicol. Appl. Pharmacol. 1990; 105: 195–208
   PubMed Web of Science ®Google Scholar
• Ramsay R. P., Rashed M. S., Nelson S. D. In vitro effects of acetaminophen metabolites and analogs on the respiration of mouse liver mitochondria. Arch. Biochem. Biophys. 1989; 273: 449–457
   PubMed Web of Science ®Google Scholar
• Holme J. A., Hongslo J. K., Bjarge C., Nelson S. D. Comparative cytotoxic effects of acetaminophen (N-acetyl-p-aminophenol), a non-hepatotoxic regioisomer acetyl-m-aminophenol and their postulated reactive hydroquinone and quinone metabolites in monolayer cultures of mouse hepatocytes. Biochem. Pharmacol 1991; 42: 1137–1142
   PubMed Web of Science ®Google Scholar
• Tirmenstein M. A., Nelson S. D. Hepatotoxicity after 3′-hydroxyacetanilide administration to buthionine sulfoximine pre-treated mice. Chem. Res. Toxicol. 1991; 4: 214–217
   PubMed Web of Science ®Google Scholar
• Dixon M. F., Dixon B., Aparicio S. R., Loney D. P. Experimental paracetamol-induced hepatic necrosis: A light- and electron-microscope, and histochemical study. J. Pathol 1975; 116: 17–29
   PubMed Web of Science ®Google Scholar
• Walker R. M., Racz W. S., McElligott M. D. Acetaminophen-induced hepatotoxicity in mice. Lab. Invest. 1980; 42: 181–189
   PubMed Web of Science ®Google Scholar
• Meyers L. L., Beierschmitt W. P., Khairallah E. A., Cohen S. D. Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice. Toxicol. Appl. Pharmacol. 1988; 93: 378–387
   PubMed Web of Science ®Google Scholar
• Katyare S. S., Satav J. G. Impaired mitochondrial oxidative energy metabolism following paracetamol-induced hepatotoxicity in the rat. Br. J. Pharmacol. 1989; 96: 51–58
   PubMed Web of Science ®Google Scholar
• Burcham P. C., Harman A. W. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J. Biol. Chem. 1991; 266: 5049–5054
   PubMed Web of Science ®Google Scholar
• Bartalone J. B., Sparks K., Cohen S. D., Khairallah E. A. Immunochemical detection of acetaminophen-bound liver proteins. Biochem. Pharmacol. 1987; 36: 1193–1196
   PubMed Web of Science ®Google Scholar
• Roberts D. W., Pumford N. R., Potter D. W., Benson R. W., Hinson J. A. A sensitive immunochemical assay for acetamino-phen-protein adducts. J. Pharmacol. Exp. Ther. 1987; 241: 527–533
   PubMed Web of Science ®Google Scholar
• Pumford N. R., Martin B. M., Hinson J. A. A metabolite of acetaminophen covalently binds to the 56 kDa selenium binding protein. Biochem. Biophys. Res. Commun. 1992; 182: 1348–1355
   PubMed Web of Science ®Google Scholar
• Bartalone J. B., Birge R. B., Bulera S. J., Bruno M. K., Nishanian E. U., Cohen S. D., Khairallah E. A. Purification, antibody production, and partial amino acid sequence of the 58-kDa ac-etaminophen-binding liver proteins. Toxicol. Appl. Pharmacol. 1992; 113: 19–29
   PubMed Web of Science ®Google Scholar
• Tirmenstein M. A., Nelson S. D. Acetaminophen-induced oxidation of protein thiols: Contribution of impaired thiol metabolizing enzymes to the breakdown of adenine nucleotides. J. Biol. Chem. 1990; 265: 3059–3065
   PubMed Web of Science ®Google Scholar
• Dietze E. C., Schafer A., Omichinski J. O., Nelson S. D.
   Google Scholar
• Dietz E. C., Schäfer A, Nelson S. D. Inactivation of glycer-aldehyde-3-phosphate dehydrogenase (GAPDH) by N-acetyl-p-benzo-quinone imine (NAPQI). The Toxicologist (Abs.) 1992; 12: 288
   Google Scholar
• Labadorios D., David M., Portmann B., Williams R. Paracetamol-induced hepatic-necrosis in the mouse: Relationship between covalent binding, hepatic glutathione depletion and the protective effect of alpha-mercaptopropionyl glycine. Biochem. Pharmacol. 1977; 26: 31–35
   PubMed Web of Science ®Google Scholar
• Moore M., Thor H., Moore G., Nelson S., Moldeus P., Orrenius S. The toxicity of acetaminophen and N-acetyl-p-benzo-quinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J. Biol. Chem 1985; 260: 13035–13040
   PubMed Web of Science ®Google Scholar
• Tee L. B. G., Boobis A. R., Hugett A. C., Davies D. S. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol. Appl. Pharmacol. 1986; 83: 294–314
   PubMed Web of Science ®Google Scholar
• Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: The protective effect of allopurinol. J. Pharmacol. Exp. Ther. 1990; 255: 935–941
   PubMed Web of Science ®Google Scholar
• Nelson S. D., Tirmenstein M. A., Rashed M. S., Myers T. G. Acetaminophen and protein thiol oxidation. 579–588, in Ref. 6
   Google Scholar
• Coles B., Wilson I., Wardman P., Hinson J. A., Nelson S. D., Ketterer B. The spontaneous and enzymic reaction of N-acetyl-p-benzoquinone imine with glutathione. Arch. Biochem. Biophys. 1988; 264: 253–260
   PubMed Web of Science ®Google Scholar
• Fernando C. R., Calder I. C., Ham K. N. Studies on the mechanism of toxicity of acetaminophen: Synthesis and reactions of N-acetyl-2,6-dimethyl- and N-acetyl-3,5-dimethyl-p-benzoquinone imines. J. Med. Chem. 1980; 23: 1153–1158
   PubMed Web of Science ®Google Scholar
• Rundgren M., Porubek D. J., Harvison P. J., Cotgreave I. A., Moldeus P., Nelson S. D. Comparative cytotoxic effects of N-acetyl-p-benzoquinone imine and two dimethylated analogues. Mol. Pharmacol 1988; 34: 566–572
   PubMed Web of Science ®Google Scholar
• Birge R. B., Bartalone J. B., Cohen S. D., Khairallah E. A., Smolin L. A. A comparison of proteins 5-thiolated by glutathione to those arylated by acetaminophen. Biochem. Pharmacol. 1991; 42: 5197–5207
   Google Scholar
• Wendel A., Feuerstein S., Konz K. -H. Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo. Biochem. Pharmacol 1979; 28: 2051–2055
   PubMed Web of Science ®Google Scholar
• Fairhurst S., Barber D. J., Clark B., Horton A. A. Studies on paracetamol-induced lipid peroxidation. Toxicology 1982; 23: 249–259
   PubMed Web of Science ®Google Scholar
• Albano E., Poli G., Charpotto E., Biasi F., Dianzani M. U. Paracetamol-stimulated lipid peroxidation in isolated rat and mouse hepatocytes. Chem.-Biol. Interact. 1983; 47: 249–263
   PubMed Web of Science ®Google Scholar
• Kyle M. E., Miccadei S., Nakae D., Farber J. L. Superoxide dismutase and catalase protect cultured hepatocytes from the cytotoxicity of acetaminphen. Biochem. Biophys. Res. Commun. 1987; 149: 889–896
   PubMed Web of Science ®Google Scholar
• Burk R. F., Lane J. M. Ethane production and liver necrosis in rats after administration of drugs and other chemicals. Toxicol. Appl. Pharmacol. 1979; 50: 467–478
   PubMed Web of Science ®Google Scholar
• Kamiyama T., Sato C., Liu J., Tajin K., Miyakawa H., Marumo F. Role of lipid peroxidation in acetaminophen-induced hepa-totoxicity: Comparison with carbon tetrachloride. Toxicol. Lett. 1993; 66: 7–12
   PubMed Web of Science ®Google Scholar
• Younes M., Siegers C. -P. The role of iron in the paracetamol-and CCl4-induced lipid peroxidation and hepatotoxiciry. Chem.-Biol. Interact. 1985; 55: 327–334
   PubMed Web of Science ®Google Scholar
• Younes M., Sause C., Siegers C. -P., Lemoine R. Effect of deferrioxamine and diethyldithiocarbamate on paracetamol-induced hepato- and nephrotoxicity. The role of lipid peroxidation. J. Appl. Toxicol. 1988; 8: 261–265
   PubMed Web of Science ®Google Scholar
• Beales D., Hue D. P., McLean A. E. M. Lipid peroxidation, protein synthesis and protection by calcium EDTA in paracetamol injury to isolated hepatocytes. Biochem. Pharmacol. 1985; 34: 19–23
   PubMed Web of Science ®Google Scholar
• Porubek D. J., Rundgren M., Harvison P. J., Nelson S. D., Moldéus P. Investigation of mechanisms of acetaminophen hepato-toxicity in isolated rat hepatocytes with the acetaminophen analogues 3,5-dimethylacetaminophen and 2,6-dimethylacetaminophen. Mol. Pharmacol. 1987; 31: 6457–6463
   Google Scholar
• Garrido A., Arancibia C., Campos R., Valenzuela A. Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: Its probable antioxidant effect is potentiated by the flavanoid silybin. Pharmacol. Toxicol. 1991; 69: 9–12
   PubMedGoogle Scholar
• Farber J. L., Leonard T. B., Kyle M. E., Nakae D., Serroni A., Rogers S. A. Peroxidation-dependent and peroxidation-indepen-dent mechanisms by which acetaminophen kills cultured rat hepatocytes. Arch. Biochem. Biophys. 1988; 267: 640–650
   PubMed Web of Science ®Google Scholar
• Rosen G. M., Singletary W. V., Jr., Rauckman E. J., Killenberg P. G. Acetaminophen hepatotoxicity. An alternative mechanism. Biochem. Pharmacol. 1983; 32: 2053–2059
   PubMed Web of Science ®Google Scholar
• Powis G., Svingen B. A., Dahlin D. C., Nelson S. D. Enzymatic and non-enzymatic reduction of N-acetyl-p-benzoquinone imine and some properties of the N-acetyl-p-benzoquinone imine radical. Biochem. Pharmacol. 1984; 33: 2367–2370
   PubMed Web of Science ®Google Scholar
• Fischer V., West P. R., Nelson S. D., Harvison P. J., Mason R. P. Formation of 4-aminophenoxyl free radical from the acetaminophen metabolite N-acetyl-p-benzoquinone imine. J. Biol. Chem. 1985; 260: 11446–11450
   PubMed Web of Science ®Google Scholar
• Bisby R. H., Tabassum N. Properties of the radicals formed by one-electron oxidation of acetaminophen—A pulse-radiolysis study. Biochem. Pharmacol. 1988; 37: 2731–2738
   PubMed Web of Science ®Google Scholar
• Ross D., Albano E., Nilsson U., Moldeus P. Thiyl radicals-Formation during peroxidase-catalyzed metabolism of acetaminophen in the presence of thiols. Biochem. Biophys. Res. Commun. 1984; 125: 109–115
   PubMed Web of Science ®Google Scholar
• Laskin D. L., Pilaro A. M. Potential role of activated macrophages in acetaminophen hepatotoxcity. Toxicol. Appl. Pharmacol 1986; 86: 204–215
   PubMed Web of Science ®Google Scholar
• Jaeschke H., Mitchell J. R. Neutrophil accumulation exacerbates acetaminophen-induced liver injury. FASEB J. 1989; 3: A920
   Google Scholar
• van de Straat R., de Vries J., Vermeulen N. P. E. Role of hepatic microsomal and purified cytochrome P-450 in one-electron reduction of two quinone imines and concomitant reduction of molecular oxygen. Biochem. Pharmacol. 1987; 36: 613–619
   PubMed Web of Science ®Google Scholar
• Elsisi A. E. D., Hall P., Sim W. -L. W., Earnest D. L., Sipes I. G. Characterization of vitamin A potentiation of carbon tetrachlo-ride-induced liver injury. Toxicol. Appl. Pharmacol. 1993; 9: 280–288
   Google Scholar
• Nakae D., Yamamoto K., Yoshiji H., Kinugasa T., Maruyama H., Farber J. L., Konishi Y. Liposome-encapsulated superoxide dismutase prevents liver necrosis induced by acetaminophen. Am. J. Pathol. 1990; 136: 787–795
   PubMed Web of Science ®Google Scholar
• Ray S. D., Sorge C. L., Raucy J. L., Corcoran G. B. Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury. Toxicol. Appl. Pharmacol. 1990; 106: 346–351
   PubMed Web of Science ®Google Scholar
• Shen W., Kamendulis L. M., Ray S. D., Corcoran G. B. Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: Effects of Ca2+ endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicol. Appl. Pharmacol. 1992; 112: 32–40
   PubMed Web of Science ®Google Scholar
• Ray S. D., Kamendulis L. M., Gurule M. W., Yorkin R. D., Corcoran G. B. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 1993; 7: 453–463
   PubMed Web of Science ®Google Scholar
• Tsokos-Kuhn J. O., Todd E. L., McMillin-Wood J. B., Mitchell J. R. ATP-dependent calcium uptake by rat liver plasma membrane vesicles: Effect of alkylating hepatotoxins in vivo. Mol. Pharmacol. 1985; 28: 56–61
   PubMed Web of Science ®Google Scholar
• Boobis A. R., Seddon C. E., Nasseri-Sina P., Davies D. S. Evidence for a direct role of intracellular calcium in paracetamol toxicity. Biochem. Pharmacol. 1990; 39: 1277–1281
   PubMed Web of Science ®Google Scholar
• Nicotera P., Rundgren M., Porubek D. J., Cotgreave I., Moldeus P., Orrenius S., Nelson S. D. On the role of Ca2+ in the toxicity of alkylating and oxidizing quinone imines in isolated hepatocytes. Chem. Res. Toxicol. 1989; 2: 46–50
   PubMed Web of Science ®Google Scholar
• Corcoran G. B., Wong B. K., Neese B. L. Early sustained rise in total liver calcium during acetaminophen toxicity in mice. Res. Commun. Chem. Pathol. Pharmacol. 1987; 58: 291–305
   PubMedGoogle Scholar
• Tsokos-Kuhn J. O. Evidence in vivo for elevation of intracellular free Ca2+ in the liver after diquat, acetaminophen, and CC14. Bio-chem. Pharmacol 1989; 38: 3061–3065
   PubMed Web of Science ®Google Scholar
• Landon E. J., Naukam R. J., Sastry B. V. Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents. Biochem. Pharmacol. 1986; 35: 697–705
   PubMed Web of Science ®Google Scholar
• Thibault N., Peytavin G., Claude J. R. Calcium channel blocking agents protect against acetaminophen-induced cytotoxicity in rat hepatocytes. J. Biochem. Toxicol. 1991; 6: 237–239
   PubMedGoogle Scholar
• Harman A. W., Mahar S. O., Burcham P. C., Madsen B. W. Level of cytosolic free calcium during acetaminophen toxicity in mouse hepatocytes. Mol. Pharmacol 1992; 41: 665–670
   PubMed Web of Science ®Google Scholar
• Hardwick S. J., Wilson J. W., Fawthrop D. J., Boobis A. R., Davies D. S. Paracetamol toxicity in hamster isolated hepatocytes: The increase in cytosolic calcium accompanies, rather than precedes, loss of viability. Arch. Toxicol 1992; 66: 408–412
   PubMed Web of Science ®Google Scholar
• Fawthrop D. J., Boobis A. R., Davies D. S. Mechanisms of cell death. Arch. Toxicol 1991; 65: 437–444
   PubMed Web of Science ®Google Scholar
• Corcoran G. B., Ray S. The role of the nucleus and other compartments in toxic cell death produced by alkylating hepa-totoxicants. Toxicol. Appl. Pharmacol 1992; 113: 167–183
   PubMed Web of Science ®Google Scholar
• Grundschober F. Literature review of pulegone. Perfum. Flavor 1979; 4: 15–17
   Google Scholar
• Hall R. A., Oser B. L. Recent progress in the consideration of flavoring ingredients under the food additives amendment III GRAS substances. Food Technol 1965; 19: 253–271
   Web of Science ®Google Scholar
• Jacobs M. L., Burlage H. M. Index of Plants of North Carolina with Reputed Medicinal Uses. 1958; 112–113
   Google Scholar
• Rose J. Herbs and Things. Grosset and Dunlap, New York 1972; 50
   Google Scholar
• Farnsworth N. R., Bingell A. S., Cordell G. A., Crane F. A., Fong H. H. S. Potential value of plants as sources of new anti-fertility agents, I. J. Pharm. Scl 1975; 64: 535–598
   PubMed Web of Science ®Google Scholar
• Riddle J. M., Estes J. W. Oral contraceptives in ancient and medieval times. Am. Scl 1992; 80: 226–233
   Web of Science ®Google Scholar
• Gleason M. N., Gosselin R. E., Hodge H. C., Smith R. P. Clinical Toxicology of Commercial Products 3rd ed. Williams and Wilkins, Baltimore 1969; 109
   Google Scholar
• Watt J. M., Breyer-Brandwijk M. G. The Medicinal and Poisonous Plants of Southern and Eastern Africa 2nd ed. E. and S. Livingston, London 1962; 523
   Google Scholar
• Vallance W. B. Pennyroyal oil poisoning: A fatal case. Lancet 1955; ii: 850–851
   Google Scholar
• Gunby P. Plant known for centuries still causes problems today. J. Am. Med. Assoc 1979; 241: 2246–2247
   PubMedGoogle Scholar
• Sullivan J. B., Rumack B. H., Thomas H., Peterson R. G., Brysch P. Pennyroyal oil poisoning and hepatotoxicity. J. Am. Med. Assoc. 1979; 242: 2873–2874
   PubMed Web of Science ®Google Scholar
• Gold J., Cates W. Herbal abortifacients. J. Am. Med. Assoc 1980; 243: 1365–1366
   PubMed Web of Science ®Google Scholar
• Gordon W. P., Forte A. J., McMurtry R. J., Gal J., Nelson S. D. Hepatotoxicity and pulmonary toxicity of pennyroyal oil and its constituent terpenes in the mouse. Toxicol. Appl. Pharmacol. 1982; 65: 413–424
   PubMed Web of Science ®Google Scholar
• Mizutani T., Nomura H., Nakanishi K., Fujita S. Effects of drug metabolism modifiers on pulegone-induced hepatotoxicity in mice. Res. Commun. Chem. Pathol. Pharmacol. 1987; 58: 75–83
   PubMedGoogle Scholar
• Thomasson D., Slattery J. T., Nelson S. D. Contribution of menthofiiran to the hepatotoxicity of pulegone: Assessment based on matched area under the curve and on matched time course. J. Pharmacol. Exp. Then 1988; 224: 825–829
   Google Scholar
• Moorthy B., Madyastha P., Madyastha K. M. Hepatotoxicity of pulegone in rats: Its effects on microsomal enzymes. in vitro, Toxicology 1989; 55: 327–337
   Google Scholar
• Nelson S. D., Gordon W. P. Mammalian drug metabolism. J. Nat. Prod. 1983; 46: 71–78
   PubMed Web of Science ®Google Scholar
• Gordon W. P., Huitric A. C., Seth C. L., McClanahan R. H., Nelson S. D. The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofiiran. Drug Metab. Dispos. 1987; 15: 589–594
   PubMed Web of Science ®Google Scholar
• Moorthy B., Madyastha P., Madyastha K. M. Metabolism of a monoterpene ketoneR-(+)-pulegone, a hepatotoxin in rat. Xeno-biotica 1989; 19: 217–224
   PubMed Web of Science ®Google Scholar
• Madyastha K. M., Raj C. P. Studies on the metabolism of a monoterpene ketone, (R)-(+)-pulegone—a hepatotoxin in rat: Isolation and characterization of new metabolites. Xenobiotica 1993; 23: 509–518
   PubMed Web of Science ®Google Scholar
• Madyastha K. M., Moorthy B. Pulegone mediated hepatotoxicity: Evidence for covalent binding of (R)-(+)-[14C]pulegone to microsomal proteins in vitro. Chem.-Biol. Interact. 1989; 72: 325–333
   PubMed Web of Science ®Google Scholar
• McClanahan R. H., Huitric A. C., Pearson P. G., Desper J. C., Nelson S. D. Evidence for a cytochrome P-450 catalyzed al-lylic rearrangement with double bond topomerization. J. Am. Chem. Soc 1988; 110: 1979–1981
   Web of Science ®Google Scholar
• Nelson S. D., McClanahan R. H., Thomassen D., Gordon W. P., Knebel N. Investigations of mechanisms of reactive metabolite formation from (R)-(+)-pulegone. Xenobiotica 1992; 22: 1157–1164
   PubMed Web of Science ®Google Scholar
• Thomassen D., Pearson P. G., Slattery J. T., Nelson S. D. Partial characterization of biliary metabolites of pulegone by tandem mass spectrometry: Detection of glucuronide, glutathione, and gluta-thionyl glucuronide conjugates. Drug Metab. Dispos. 1991; 19: 997–1003
   PubMed Web of Science ®Google Scholar
• McClanahan R. H., Thomassen D., Slattery J. T., Nelson S. D. Metabolic activation of (R)-(+)-pulegone to a reactive enonal that covalently binds to mouse liver proteins. Chem. Res. Toxicol 1989; 2: 349–355
   PubMed Web of Science ®Google Scholar
• Madyastha K. M., Raj C. P. Biotransformation of R-(+)-pule-gone and menthofuran in vitro: Chemical basis for toxicity,. Bio-chem. Biophys. Res. Commun. 1990; 173: 1086
   PubMed Web of Science ®Google Scholar
• Thomassen D., Knebel N., Slattery J. T., McClanahan R. H., Nelson S. D. Reactive intermediates in the oxidation of menthofuran by cytochromes P-450. Chem. Res. Toxicol. 1992; 5: 123–130
   PubMed Web of Science ®Google Scholar
• Madyastha K. M., Raj C. P. Metabolic fate of menthofuran in rats: Novel oxidative pathways. Drug Metab. Dispos. 1992; 20: 295–301
   PubMed Web of Science ®Google Scholar
• Oishi S., Nelson S. D. Evidence for the formation of heterocyclic arene oxides and a γ-ketoenal by reaction of menthofuran with dimethyldioxirane. J. Org. Chem. 1992; 57: 2744–2747
   Web of Science ®Google Scholar
• Oishi S., Nelson S. D., unpublished results
   Google Scholar
• Skiles G. L., Oishi S., Nelson S. D. Epitope characterization of an anti-menthofuran antibody and the use of the antibody in identification of rat hepatic protein menthofuran adducts,. Toxicologist 1994; 14: 112
   Google Scholar
• Williams A. T., Burk R. F. Carbon tetrachloride hepatotoxicity: An example of free radical-mediated injury. Semin. Liver Dis. 1990; 10: 279–284
   PubMed Web of Science ®Google Scholar
• Lau S. S., Monks T. J. The contribution of bromobenzene to our current understanding of chemically-induced toxicities. Life Sci. 1988; 42: 1259–1269
   PubMed Web of Science ®Google Scholar
• Slaughter D. E., Hanzlik R. P. Identification of epoxide-and quinone-derived bromobenzene adducts to protein sulfur nucleo-philes. Chem. Res. Toxicol. 1991; 4: 349–359
   PubMed Web of Science ®Google Scholar
• Rombach E. M., Zheng J., Hanzlik R. P. Covalent binding of epoxide and quinone bromobenzene metabolites to proteins: Recognition and discrimination with specific antibodies,. Toxicologist 1994; 14: 429
   Google Scholar
• Rao K. S., Recknagel R. O. Early incorporation of carbon-labeled carbon tetrachloride into rat liver particulate lipids and proteins. Exp. Mol. Pathol. 1969; 10: 219–228
   PubMed Web of Science ®Google Scholar
• Smith C. V. Evidence for participation of lipid peroxidation and iron in diquat-induced hepatic necrosis in vivo. Mol. Pharmacol. 1987; 32: 417–422
   PubMed Web of Science ®Google Scholar
• Keller R. J., Halmes N. C., Hinson J. A., Pumford N. R. Immunochemical detection of oxidized proteins. Chem. Res. Toxicol. 1993; 6: 430–433
   PubMed Web of Science ®Google Scholar