The depressant effect of interferon-alpha on drug metabolizing activity in the liver has been investigated in 12 patients with chronic active hepatitis B. 7-methoxy-coumarin (7-MC) O-demethylase and 7-ethoxycoumarin (7-EC) O-deethylase, in specimens obtained by liver biopsy, were measured before and after interferon treatment. 7-MC and 7-EC O-dealkylase activity were significantly reduced after interferon treatment, from 13.4 to 9.24 nmol.g-1 liver.min-1, and from 3.22 to 2.16 nmol.g-1 liver.min-1, respectively. The magnitude of the fall varied widely between individual patients. The study provides the first direct evidence that interferon-alpha can impair the activity of drug metabolizing enzymes in the human liver.

AIM:To investigate the total cytochrome P450 (CYP) content, microsomal mixed-function oxidase (MFO) activity, and expression of mRNAs for various CYP isozymes in a simple rat model of reversible obstructive jaundice. METHODS:Obstructive jaundice was created in male rats by causing bile duct obstruction with polyester tape. In another group of rats, bile duct obstruction was followed by internal biliary drainage after releasing the tape. The expression of various CYP isozyme mRNAs was semi-quantitatively assessed by competitive RT-PCR. RESULTS:The total CYP content and microsomal MFO activity showed a significant decrease after biliary obstruction, but returned to respective control levels after biliary drainage. A marked reduction in the expression of CYP1A2, 2B1/2, 2C11, 2E1, 3A1, and 3A2 mRNA was detected during biliary obstruction, while expression increased significantly toward the control level after biliary drainage. Although expression of CYP4A1 mRNA showed no reduction during biliary obstruction, it still increased significantly after biliary drainage. CONCLUSION:These results suggest that not only obstructive jaundice, but also the subsequent internal biliary drainage may affect regulatory medications of the synthesis of individual CYP isozymes differently.

Abstract-The drug metabolizing activity of rat liver during long-term adminis tration of carbon tetrachloride (CC14), and its relationship with the content of hydroxyproline (Hyp) in the liver were examined. The contents of cytochrome P-450 (P-450) and cytochrome b5 (b5) and the metabolization of aniline, aminopyrine, 7-ethoxycoumarin (7-EC) and benzo(a)pyrene (B(a)P) in the microsomal fraction were examined five days after the final administration of CC14. The contents of P-450 and b5 and the activity to metabolize the four substrates were gradually reduced as the Hyp content in the liver increased. However, aminopyrine N-demethylation and B(a)P hydroxylation, particularly the latter, was more reduced than aniline hydroxylation and 7-EC 0-deethylation in the early stage of hepatic fibrosis. Such differences may be due mainly to the different P-450 subtypes affected by CC14.

Abstract-The effects of six inducers and malotilate on 7-alkoxycoumarin 0 dealkylase activities in rat liver microsomes were examined. Phenobarbital (PB) (100 mg/kg) was administered intraperitoneally to rats for 6 days; 3-methylcholan threne (3-MC) (40 mg/kg), e9-naphthoflavone ((3-NF) (40 mg/kg), isosafrole (150 mg/kg) and polychlorinated biphenyls (PCB) (100 mg/kg) were administered intraperitoneally for 3 days; isoniazid (INH) (50 mg/kg) was administered intra peritoneally for 10 days; and malotilate (500 mg/kg) was administered orally for 3 days. The 0-dealkylase activities toward 7-methoxycoumarin (7-MC), 7 ethoxycoumarin (7-EC) and 7-propoxycoumarin (7-PC) were examined 24 hr after the final administration of the drugs. The ratios of 7-EC 0-deethylase and 7 PC 0-depropylase to 7-MC 0-demethylase activity in the control and six inducer treated groups were compared. The ratios in the groups treated with the six com pounds, each of which induces a different form(s) of cytochrome P-450 (P-450), were clearly different from each other. Therefore, the measurement of 7-alkoxy coumarin 0-dealkylase activities should be extremely useful for the routine deter mination of the molecular species of P-450. On the other hand, the ratio in the malotilate-treated group was different from that in any other inducer-treated group, so that there might be a possibility that malotilate induced a form(s) of P-450 that is different from any of the already known species.

The depressant effect of interferon beta on drug-metabolizing activity in the human liver was investigated. Seven patients with chronic hepatitis C were treated with interferon beta at doses of 3 x 10(6) to 9 x 10(6) IU/day for 8 wk. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Theophylline pharmacokinetics were also examined before and after interferon treatment. Interferon beta treatment reduced the activities of both O-dealkylases from 6.0 (100%) to 3.2 (53%) nmol/gm liver per minute and from 1.9 (100%) to 1.1 (58%) nmol/gm liver per minute, respectively (p < 0.05). The total body clearance of theophylline was also decreased (from 0.76 to 0.56 ml/kg/min; p < 0.05), and its elimination half-life was increased (from 8.4 to 11.7 hr; p < 0.05); however, the volume of distribution was not significantly affected. The magnitude of the decreases in enzyme activities and in theophylline clearance varied widely in individual patients and did not correlate with the dose of interferon administered. This study provides the first direct evidence that interferon beta can depress the activity of drug-metabolizing enzymes in the human liver.