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Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

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Abstract

Cocaine is an intrinsic hepatotoxin in laboratory animals, and there is growing evidence that high doses of cocaine can precipitate hepatic necrosis in humans. The rodent model of cocaine hepatotoxicity is commensurate with the concept that a multistep, mainly cytochrome P-450 dependentN-oxidative pathway is responsible for the expression of hepatocellular injury. Among the possible biomechanisms by which cocaine exerts its cytotoxic effects, direct oxidative damage by reactive oxygen species generated by redox cycling during the metabolic cascade seems most important. The role of the ensuing lipid peroxidation and protein thiol oxidatioin is less clear. Similarly, the functional role of irreversible (covalent) binding of a not yet defined electrophilic cocaine intermediate to hepatocellular proteins remains enigmatic so long as the critical molecular targets have not been identified. Finally, glutathione plays a pivotal protective role against cocaine-induced hepatic injury. Interactions with ethanol or inducers of the expression of the cytochrome P-450IIB subfamily can potentiate cocaine hepatotoxicity. Thus, the net amount of the ultimate reactive species seems to determine the severity of the hepatic lesions and to be responsible for the marked interspecies, interstrain, and sex differences. Recent advances in culture techniques of hepatocytes and precision-cut liver slices from various species including man have made it possible to correlate cocaine biotransformation with cytotoxicity and to selectively study the putative cellular mechanisms. Clearly, more studies are necessary to further illuminate our understanding of the role of the biochemical and molecular events precipitating hepatic necrosis during cocaine-mediated hepatotoxicity.

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References

  • Abelson HI, Miller JD (1985) A decade of trends in cocaine use in the household population. Natl Inst Drug Abuse Res Mongr Ser 61: 35–49

    Google Scholar 

  • Ambre J, Ruo TI, Nelson J, Belknap S (1988) Urinary excretion of cocaine, benzoylecgonine, and ecgonine methyl ester in humans. J Anal Toxicol 12: 301–306

    Google Scholar 

  • Bartolone JB, Birge RB, Sparks K, Cohen SD, Khairallah EA (1988) Immunochemical analysis of acetaminophen covalent binding to proteins. Partial characterization of the major acetaminophen-binding liver proteins. Biochem Pharmacol 37: 4763–4774

    Google Scholar 

  • Basmadjian GP, Mills SL, Kanvinde M, Basmadjian NP (1990) Structure biodistribution relationship of radioiodinated tropeines: search for a molecular probe for the characterization of the cocaine receptor. J Labelled Comp Radiopharm 28: 801–810

    Google Scholar 

  • Benuck M, Reith MEA, Lajtha A (1988) Presence of the toxic metaboliteN-hydroxy-norcocaine in brain and liver of the mouse. Biochem Pharmacol 37: 1169–1172

    Google Scholar 

  • Birge RB, Bartolone JB, Hart SGE, Nishanian EV, Tyson CA, Khairallah EA, Cohen SD (1990) Acetaminophen hepatotoxicity: correspondence of selective protein arylation in human and mouse liver in vitro, in culture, and in vivo. Toxicol Appl Pharmacol 105: 472–482

    Google Scholar 

  • Boelsterli UA, Göldlin C, Bouis P (1990) Irreversible binding of cocaine to hepatic microsomes from ethanol- or phenobarbital-induced rats: role of P-450IIE1. Hepatology 12: 931

    Google Scholar 

  • Boelsterli UA, Atanasoski S, Göldlin C (1991) Ethanol-induced enhancement of cocaine bioactivation and irreversible protein binding: evidence against a role of cytochrome P-450IIE1. Alcoholism: Clin Exp Res (in press)

  • Boja JW, Carroll FI, Rahman MA, Philip A, Lewin AH, Kuhar MJ (1990) New, potent cocaine analogs: ligand binding and transport studies in rat striatum. Eur J Pharmacol 184: 329–332

    Google Scholar 

  • Bouis P, Boelsterli UA (1990) Modulation of cocaine metabolism in primary rat hepatocyte cultures: effects on irreversible binding and protein biosynthesis. Toxicol Appl Pharmacol 104: 429–439

    Google Scholar 

  • Bouis P, Taccard G, Boelsterli UA (1990) Determination of cocaine and norcocaine in plasma and cell cultures using high-performance liquid chromatography. J Chromatogr Biomed Appl 526: 447–459

    Google Scholar 

  • Boyer CS, Petersen DR (1990) Potentiation of cocaine-mediated hepatotoxicity by acute and chronic ethanol. Alcoholism: Clin Exp Res 14: 28–31

    Google Scholar 

  • Boyer CS, Ross D, Petersen DR (1988) Sex and strain differences in the hepatotoxic response to acute cocaine administration in the mouse. J Biochem Toxicol 3: 295–307

    Google Scholar 

  • Boyer CS, Rider P, Petersen DR (1990) Enhancement of cocaine hepatotoxicity by acute ethanol in the mouse: the possible role of xanthine oxidase. Hepatology 12: 1008

    Google Scholar 

  • Charkoudian JC, Shuster L (1985) Electrochemistry of norcocaine nitroxide and related compounds: Implications for cocaine hepatotoxicity. Biochem Biophys Res Commun 130: 1044–1051

    Google Scholar 

  • Connors S, Rankin DR, Gandolfi AJ, Krumdieck CL, Koep LJ, Brendel K (1990) Cocaine hepatotoxicity in cultured liver slices: a species comparison. Toxicology 61: 171–183

    Google Scholar 

  • Coon MJ, Koop DR (1987) Alcohol-inducible cytochrome P-450 (P-450ALC). Arch Toxicol 60: 16–21

    Google Scholar 

  • Donnelly DA, Boyer CS, Petersen DR, Ross D (1988) Cocaine-induced biochemical changes and cytotoxicity in hepatocytes isolated from both mice and rats. Chem Biol Interact 67: 95–104

    Google Scholar 

  • Ekström G, Ingelman-Sundberg M (1989) Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem Pharmacol 38: 1313–1319

    Google Scholar 

  • Englert LF, Estevez VS, Ho BT (1976) Demethylation in rats chronically treated with cocaine. Res Commun Chem Pathol Pharmacol 13: 555–558

    Google Scholar 

  • Evans MA (1983) Role of protein binding in cocaine-induced hepatic necrosis. J Pharmacol Exp Ther 224: 73–79

    Google Scholar 

  • Evans MA, Harbison RD (1978) Cocaine-induced hepatic necrosis in mice. Toxicol Appl Pharmacol 45: 739–754

    Google Scholar 

  • Evans MA, Johnson ME (1981) The role of a reactive nitroxide radical in cocaine-induced hepatic necrosis. Fed Proc 40: 638

    Google Scholar 

  • Farber JL, Kyle ME, Coleman JB (1990) Biology of disease: mechanisms of cell injury by activated oxygen species. Lab Invest 62: 670–679

    Google Scholar 

  • Farrar HC, Kearns GL (1989) Cocaine: clinical pharmacology and toxicology. J Pediatr 115: 665–675

    Google Scholar 

  • Fernandez-Checa JC, Ookhtens M, Kaplowitz N (1987) Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux and responses to incubation with ethanol. J Clin Invest 80: 57–62

    Google Scholar 

  • Fleming JA, Byck R, Barash PG (1990) Pharmacology and therapeutic applicatons of cocaine. Anesthesiology 73: 518–531

    Google Scholar 

  • Freeman RW, Harbison RD (1981a) Hepatic periportal necrosis induced by chronic administration of cocaine. Biochem Pharmacol 30: 777–783

    Google Scholar 

  • Freeman RW, Harbison RD (1981b) The role of benzoylmethylecgonine in cocaine-induced hepatotoxicity. J Pharmacol Exp Ther 218: 558–567

    Google Scholar 

  • Göldlin C, Boelsterli UA (1991a) Reactive oxygen species promote cocaine-induced cytotoxicity in cultured rat hepatocytes (abstract). Experientia 47: A32

    Google Scholar 

  • Göldlin C, Boelsterli UA (1991 b) Reactive oxygen species and non-peroxidative mechanisms of cocaine-induced cytotoxicity in cultured rat hepatocytes. Toxicology (in press)

  • Gottfried MR, Kloss MW, Graham D, Rauckman EJ, Rosen GM (1986) Ultrastructure of experimental cocaine hepatotoxicity. Hepatology 6: 299–304

    Google Scholar 

  • Grant BF, Harford TC (1990) Concurrent and simultaneous use of alcohol with cocaine: results of national survey. Drug Alcohol Depend 25: 97–104

    Google Scholar 

  • Guengerich FP, Liebler DC (1985) Enzymatic activation of chemicals to toxic metabolites. CRC Crit Rev Toxicol 14: 259–307

    Google Scholar 

  • Hearn WL, Flynn DD, Hime GW, Rose S, Cofino JC, Mantero-Atienza E, Wetli CV, Mash DC (1991) Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter. J Neurochem 56: 698–701

    Google Scholar 

  • Inaba T, Stewart DJ, Kalow W (1978) Metabolism of cocaine in man. Clin Pharmacol Ther 23: 547–552

    Google Scholar 

  • James RC, Schiefer MA, Roberts SM, Harbison RD (1987) Antagonism of cocaine-induced hepatotoxicity by the alpha-adrenergic antagonists phentolamine and yohimbine. J Pharmacol Exp Ther 242: 726–732

    Google Scholar 

  • Jindal SP, Lutz T (1986) Ion cluster techniques in drug metabolism: use of a mixture of labeled and unlabeled cocaine to facilitate metabolite identification. J Anal Toxicol 10: 150–155

    Google Scholar 

  • Jindal SP, Lutz T, Vestergaard P (1978) Mass spectrometric determination of cocaine and its biologically active metabolite, norcocaine, in human urine. Biomed Mass Spectrom 5: 658–663

    Google Scholar 

  • Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41: 3–52

    Google Scholar 

  • Johansson I, Ekström G, Scholte B, Puzycki D, Jörnvall H, Ingelman-Sundberg M (1988) Ethanol-, fasting-, and acetone-inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE subfamilies. Biochemistry 27: 1925–1934

    Google Scholar 

  • Kanel GC, Cassidy W, Shuster L, Reynolds TB (1990) Cocaine-induced liver cell injury: comparison of morphological features in man and experimental models. Hepatology 11: 646–651

    Google Scholar 

  • Kloss MW, Cavagnaro J, Rosen GM, Rauckman EJ (1982a) Involvement of FAD-containing monooxygenase in cocaine-induced hepatotoxicity. Toxicol Appl Pharmacol 64: 88–93

    Google Scholar 

  • Kloss MW, Rosen GM, Rauckman EJ (1982b) Acute cocaine-induced hepatotoxicity in DBA/2Ha male mice. Toxicol Appl Pharmacol 65: 75–83

    Google Scholar 

  • Kloss MW, Rosen GM, Rauckman EJ (1983a)N-Demethylation of cocaine to norcocaine. Evidence for participation by cytochrome P-450 and FAD-containing monooxygenase. Mol Pharmacol 23: 482–485

    Google Scholar 

  • Kloss MW, Rosen GM, Rauckman EJ (1983b) Evidence of enhanced in vivo lipid peroxidation after acute cocaine administration. Toxicol Lett 15: 65–70

    Google Scholar 

  • Kloss M, Rosen GM, Rauckman EJ (1984) Cocaine-mediated hepatotoxicity. A critical review. Biochem Pharmacol 33: 169–173

    Google Scholar 

  • Kokko JP (1990) Metabolic and social consequences of cocaine abuse. Am J Med Sci 229: 361–365

    Google Scholar 

  • Kreek MJ, Stimmel B (1984) Alcoholism and Polydrug Use, Haworth Press, New York

    Google Scholar 

  • Leibman D, Smolen A, Smolen TN (1990) Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice. Pharmacol Biochem Behav 37: 161–165

    Google Scholar 

  • Lieber CS (1990) Interaction of ethanol with drugs, hepatotoxic agents, carcinogens and vitamins. Alcohol Alcohol 25: 157–165

    Google Scholar 

  • Loper KA (1989) Clinical toxicology of cocaine. Med Toxicol Adverse Drug Exp 4: 174–185

    Google Scholar 

  • Lowry WT, Lomonte JN, Hatchett D, Garriott JC (1979) Identification of two novel cocaine metabolites in bile by gas chromatography and gas chromatography/mass spectrometry in a case of acute intravenous cocaine overdose. J Anal Toxicol 3: 91–95

    Google Scholar 

  • Marks V, Chapple PAL (1967) Hepatic dysfunction in heroin and cocaine users. Br J Addict 62: 189–195

    Google Scholar 

  • Monks TJ, Lau SS (1988) Reactive intermediates and their toxicological significance. Toxicology 52: 1–53

    Google Scholar 

  • Nayak PK, Misra AL, Mulé SJ (1976) Physiological disposition and biotransformation of [3H]cocaine in acutely and chronically treated rats. J Pharmacol Exp Ther 196: 556–569

    Google Scholar 

  • Nelson SD, Pearson PG (1990) Covalent and noncovalent interactions in acute lethal cell injury caused by chemicals. Annu Rev Pharmacol Toxicol 30: 169–195

    Google Scholar 

  • Perino LE, Warren GH, Levine JS (1987) Cocaine-induced hepatotoxicity in humans. Gastroenterology 93: 176–180

    Google Scholar 

  • Peterson FJ, Knodell RG, Lindemann NJ, Steele NM (1983) Prevention of acetaminophen and cocaine hepatotoxicity in mice by cimetidine treatment. Gastroenterology 85: 122–129

    Google Scholar 

  • Powell CJ, Charles SJ (1990) Phenobarbital (PB) and butylated hydroxytoluene (BHT) interactively modulate cocaine hepatotoxicity. Hum Exp Toxicol 9: 340–341

    Google Scholar 

  • Rafla FK, Epstein RL (1979) Identification of cocaine and its metabolites in human urine in the presence of ethyl alcohol. J Anal Toxicol 3: 59–63

    Google Scholar 

  • Rauckman EJ, Rosen GM (1982) Free radical aspects of cocaine metabolism and toxicity. In: Sato R, Kato R (eds) Microsomes and drug oxidations and drug toxicity, vol 4. Japan Scientific Societies Press, Tokyo, pp 453–462

    Google Scholar 

  • Rauckman EJ, Kloss MW, Rosen GM (1982a) Involvement of nitroxide radicals in cocaine-induced hepatotoxicity. Can J Chem 60: 1614–1620

    Google Scholar 

  • Rauckman EJ, Rosen GM, Cavagnaro J (1982b) Norcocaine nitroxide: a potential hepatotoxic metabolite of cocaine. Mol Pharmacol 21: 458–463

    Google Scholar 

  • Reed DJ (1990) Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol 30: 603–631

    Google Scholar 

  • Roberts SM, Pounds JG, James RC (1990) Cocaine toxicity in cultured rat hepatocytes. Toxicol Lett 50: 283–288

    Google Scholar 

  • Rosen GM, Kloss MW, Rauckman EJ (1982) Initiation of in vitro lipid peroxidation byN-hydroxynorcocaine and norcoaine nitroxide. Mol Pharmacol 22: 529–531

    Google Scholar 

  • Rossi (1990) Cocain and Cocain-Intoxikation. Dtsch Med Wschr 115: 868–873

    Google Scholar 

  • Shuster L, Thompson ML (1985) Epinephrine and liver damage from cocaine. Pharmacologist 27: 200

    Google Scholar 

  • Shuster L, Quimby F, Bates A, Thompson ML (1977) Liver damage from cocaine in mice. Life Sci 20: 1035–1042

    Google Scholar 

  • Shuster L, Casey E, Welankiwar SS (1983) Metabolism of cocaine and norcocaine toN-hydroxynorcocaine. Biochem Pharmacol 32: 3045–3051

    Google Scholar 

  • Smith AC, Freeman RW, Harbison RD (1981) Ethanol enhancement of cocaine-induced hepatotoxicity. Biochem Pharmacol 30: 453–458

    Google Scholar 

  • Smith RM (1984a) Arylhydroxy metabolites of cocaine in the urine of cocaine users. J Anal Toxicol 8: 35–37

    Google Scholar 

  • Smith RM (1984b) Ethyl esters of arylhydroxy- and arylhydroxymethoxycocaines in the urines of simultaneous cocaine and ethanol users. J Anal Toxicol 8: 38–42

    Google Scholar 

  • Smith RM, Poquette MA, Smith PJ (1984) Hydroxymethoxybenzoyl-methylecgonines: new metabolites of cocaine from human urine. J Anal Toxicol 8: 29–34

    Google Scholar 

  • Smolen TN, Smolen A (1990) Developmental expression of cocaine hepatotoxicity in the mouse. Pharmacol Biochem Behav 36: 333–338

    Google Scholar 

  • Stewart DJ, Inaba T, Lucassen M, Kalow W (1979) Cocaine metabolism: cocaine and norcocaine hydrolysis by liver and serum esterases. Clin Pharmacol Ther 25: 464–468

    Google Scholar 

  • Suarez KA, Bhonsle P, Richardson DL (1986) Protective effect of N-acetylcysteine pretreatment against cocaine induced hepatotoxicity and lipid peroxidation in the mouse. Res Commun Subst Abuse 7: 7–18

    Google Scholar 

  • Tabasco-Minguillan J, Novick DM, Kreek MJ (1990) Liver function tests in non-parenteral cocaine users. Drug Alcohol Depend 26: 169–174

    Google Scholar 

  • Teaf CM, Freeman RW, Harbison RD (1984) Cocaine-induced hepatotoxicity: lipid peroxidation as a possible mechanism. Drug Chem Toxicol 7: 383–396

    Google Scholar 

  • Thompson ML, Shuster L, Shaw K (1979) Cocaine-induced necrosis in mice. The role of cocaine metabolism. Biochem Pharmacol 28: 2389–2395

    Google Scholar 

  • Thompson ML, Shuster L, Casey E, Kanel GC (1984) Sex and strain differences in response to cocaine. Biochem Pharmacol 33: 1299–1307

    Google Scholar 

  • Wanless IR, Dore S, Gopinath N, Tan J, Cameron R, Heathcote EJ, Blendis LM, Levy G (1990) Histopathology of cocaine hepatotoxicity. Report of four patients. Gastroenterology 98: 497–501

    Google Scholar 

  • Watanabe HK, Hoskins B, Ho IK (1987) Sensitivity difference to hepatotoxicity of cocaine in spontaneously hypertensive and Wistar Kyoto rats. Alcohol Drug Res 7: 363–370

    Google Scholar 

  • Watanabe HK, Hoskins B, Ho IK (1988) Effects of subacute treatment with cocaine on activities of N-demethylase, UDP-glucuronyl-transferase and sulfotransferase in WKY and SHR rat liver — sex and strain differences. Life Sci 42: 79–86

    Google Scholar 

  • Welder AA, Smith MA, Ramos K, Acosta D (1988) Cocaine-induced cardiotoxicity in vitro. Toxicol in vitro 2: 205–213

    Google Scholar 

  • Welder AA, O'Dell JF, Melchert RB, Eselin JA (1991) Evaluation of the combined toxic effects of cocaine and alcohol on primary myocardial cell cultures. In Vitro Toxicol (in press)

  • Werner G (1961) Untersuchungen zum Stoffwechsel von Tropan-Alkaloiden bei einigen Säugetieren. Planta Med 9: 293–316

    Google Scholar 

  • Wiener HL, Reith MEA (1990) Differential effects of daily administration of cocaine on hepatic and cerebral glutathione in mice. Biochem Pharmacol 40: 1763–1768

    Google Scholar 

  • Yuno K, Yamada H, Oguri K, Yoshimura H (1990) Substrate specificity of guinea pig liver flavin-containing monooxygenase for morphine, tropane and strychnos alkaloids. Biochem Pharmacol 40: 2380–2382

    Google Scholar 

  • Zhang JY, Foltz RL (1990) Cocaine metabolism in man: identification of four previously unreported cocaine metabolites in human urine. J Anal Toxicol 14: 201–205

    Google Scholar 

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  1. Institute of Toxicology, ETH and University of Zurich, Schorenstrasse 16, CH-8603, Schwerzenbach, Switzerland

    Urs A. Boelsterli & Christian Göldlin

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  1. Urs A. Boelsterli
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Dedicated to Professor Dr. Gerhard Zbinden on the occasion of his retirement

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Boelsterli, U.A., Göldlin, C. Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites. Arch Toxicol 65, 351–360 (1991). https://doi.org/10.1007/BF02284256

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