Correlations between cytochrome P-450 and oxidative metabolism of benzo[a]pyrene and 7-ethoxycoumarin in human liver in vitro and antipyrine elimination in vivo.
Cytochrome P-450 content was correlated to aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-de-ethylase activities in human liver biopsy samples in vitro. Antipyrine half-life and clearance were measured in the same patients in vivo. The results were compared with data obtained in rat liver in vitro. The correlation of cytochrome P-450 content with aryl hydrocarbon hydroxylase activity in human liver biopsy samples was relatively good (r = 0.75, p < 0.001), but that with 7-ethoxycoumarin O-de-ethylase activity was much poorer (r = 0.42, p < 0.001). The good correlation between cytochrome P-450 content and aryl hydrocarbon hydroxylase activity in biopsy samples from patients with widely varying hepatic disease processes, exposure to inducers, history of cigarette smoking, etc., is in contrast with the data obtained in the rat, where the corresponding correlation in a population treated with different inducers and inhibitors was rather poor (r = 0.37, p < 0.01). This poor correlation was caused mainly by the nonequal effects of polycyclic aromatic hydrocarbons on cytochrome P-450 and aryl hydrocarbon hydroxylase. Cigarette smoking was not found to induce human liver drug or carcinogen metabolism. Aryl hydrocarbon hydroxylase activity in vitro and antipyrine half-life or clearance in vivo were correlated (r = 0.36, p < 0.01 and r = 0.35, p < 0.01, respectively), indicating a weak, but statistically significant association between these parameters. This study suggests that correlations between in vitro and in vivo measurements of drug metabolism are not strong enough for the tests to be used as predictive tests in experimental or clinical research.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D000983:Antipyrine / Q000097:blood / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001579:Benzopyrene Hydroxylase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity
D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001579:Benzopyrene Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D000983:Antipyrine