RELATIONSHIP BETWEEN OXIDATIVE-METABOLISM OF 2-ACETYLAMINOFLUORENE, DEBRISOQUINE, BUFURALOL, AND ALDRIN IN HUMAN-LIVER MICROSOMES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (12) , 5692-5697
Abstract
The capacity of human liver microsomes from 28 individuals to metabolize debrisoquine and bufuralol, 2 drugs oxidized polymorphically in humans, as well as the carcinogen 2-acetylaminofluorene (AAF), was determined. In addition, the cytochrome P-450 content and the capacity of these microsomes to carry out the epoxidation of aldrin were measured. Interindividual differences in debrisoquine 4-hydroxylation, bufuralol 1-hydroxylation and aldrin epoxidation were 12-, 20- and 2.4-fold, respectively. The metabolism of debrisoquine was not correlated with cytochrome P-450 content (r = 0.26), whereas both the metabolism of bufuralol (r = 0.45; r2 = 0.20) and the epoxidation of aldrin (r = 0.72; r2 = 0.52) were correlated. Rates of debrisoquine and bufuralol metabolism were significantly correlated (r = 0.73), whereas only weak correlations existed between debrisoquine:aldrin (r = 0.49) and bufuralol:aldrin (r = 0.51). Because biphasic kinetics have been observed in human liver microsomes for thr 7- and 5-hydroxylation of AAF, 2 concentrations of this substrate were used. The disappearance of AAF at either 0.37 or 50 .mu.M was not correlated with debrisoquine, bufuralol, or aldrin metabolism. Similarly, at 0.37 .mu.M AAF, no correlation existed between the formation of N-, 1-, 3-, 5-, 7- and 9-hydroxylation products of AAF and debrisoquine, bufuralol, or aldrin metabolism. At 50 .mu.M AAF, only the 7-hydroxylation of this substrate correlated with bufuralol metabolism (r = 0.47). This lack of, or weak correlation between pathways leading to metabolic activation (N-hydroxylation) or detoxication (C-hydroxylation) of the carcinogen AAF and debrisoquine, bufuralol and aldrin metabolism strongly suggests that different forms of cytochrome P-450 are involvee in these pathways. In contrast, exceptionally high correlations (r > 0.94) existed between N-OH-AAF:1-OH-AAF, N-OH-AAF:7-OH-AAF and 7-OH-AAF:1-OH-AAF at the low concentration of AAF and imply that similar forms of cytochrome P-450 produce these metabolites. At 50 .mu.M AAF, these correlations are considerably weaker and explain < 35% of the variance in the data. Common cytochrome P-450 isoenzymes evidently are involved in the formation of AAF metabolites, while the metabolism of debrisoquine, bufuralol and aldrin is unrelated to the metabolism of this carcinogen in human liver microsomes.