Unimpaired induction of drug-metabolizing enzymes in hepatocytes isolated from rats with micronodular cirrhosis.
To test further the competence of the cirrhotic liver to metabolize xenobiotics, hepatocytes were isolated from control and CCl4-induced cirrhotic male or female rats. Histologically micronodular cirrhosis was present in all CCl4-treated rats, while control rats had normal livers. Portal perfusion pressure and intrahepatic collagen content were also significantly increased by CCl4 administration. In male rats, no significant differences in levels of circulating transaminases nor in alkaline phosphatase was observed between cirrhotic and control rats, while CCl4-treated females had slightly higher than normal serum transaminase levels at the time of the studies. Hepatocytic cytochrome P-450 and basal xenobiotic biotransformation were unaffected by micronodular cirrhosis in both genders; calculation of the aminopyrine and 7-ethoxycoumarin intrinsic clearances (Cli) revealed, however, a slightly decreased transformation potential in hepatocytes obtained from cirrhotic females, a phenomenon not observed in cirrhotic male rats. It is speculated that the observed reduction in Cli may have been independent of cirrhosis per se, owing to the perduring cytotoxic effect of CCl4 as evidenced by the higher than normal level of transaminases in female rats. Finally, male rats were subjected to in vivo administration of phenobarbital or 3-methylcholanthrene; both compounds led to significant induction of the mixed-function oxidase system, which was similar in magnitude and in selectivity in control and cirrhotic rats as illustrated by calculation of the Michaelis-Menten kinetic parameters for aniline p-hydroxylation, aminopyrine-N-demethylation, 7-ethoxycoumarin-O-deethylation, and p-nitrophenol UDP-glucuronyl transferase. We conclude that in well-established but compensated and hepatolysis-free micronodular cirrhosis, hepatocytes are fully able to transform xenobiotics and to respond normally and selectively to inducers of drug metabolism.
Wu
Z Q
ZQ
Centre de recherche clinique André-Viallet, Hôpital St-Luc, Montréal, Québec, Canada.
Piché
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Vallières
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Huet
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Gascon-Barré
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D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis; D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis; D000815:Aniline Hydroxylase / Q000096:biosynthesis; D000818:Animals; D001711:Biotransformation; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015262:Xenobiotics / Q000378:metabolism
D015262:Xenobiotics; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D010634:Phenobarbital