Use of drugs in the evaluation of carcinogen metabolism in man

The plasma concentration or half life of a nontoxic drug metabolized by the same enzyme(s) that metabolize an environmental carcinogen may serve as an indirect index of individuality in the metabolism of the carcinogen in humans. In pursuit of this goal, we have initiated a programme on the comparative metabolism of drugs and carcinogens by human tissues. The comparative metabolism of benzo[α]pyrene (BP) and 7 ethoxycoumarin was studied in placentas from 12 women who smoked cigarettes and in the placentas from 12 nonsmokers. Although an induced level of BP hydroxylase activity was found in each placenta obtained from women who smoked cigarettes during pregnancy, 7 ethoxycoumarin O dealkylase activity was induced (about twofold) only in placentas whose BP hydroxylase activity was markedly induced (50 to 100 fold). BP hydroxylase activity in homogenates from 10 human autopsy livers correlated highly with zoxazolamine hydroxylase (r= 0.89; p<0.001), coumarin hydroxylase (r= 0.84; p <0.0025) and hexobarbital hydroxylase (r = 0.84; p < 0.0025) activities. A borderline correlation was observed between the dealkylation of 7 ethoxycoumarin and the hydroxylation of BP (r= 0.60; p < 0.05), and no correlation was observed between the hydroxylation of antipyrine and BP in the human livers. Similarly, antipyrine metabolism did not correlate with the hydroxylation of zoxazolamine, coumarin, hexobarbital, or the dealkylation of 7 ethoxycoumarin. However, if fetal and newborn livers were not included in the statistical analysis of the data, the metabolism of antipyrine appears to correlate with that of BP and the other drugs. The results of our studies suggest the presence of several hydroxylating systems in the liver samples studied. Studies on epoxide hydrase activity in the human autopsy livers revealed that styrene oxide hydrase activity in microsomes correlated highly with octene oxide hydrase, phenanthrene 9,10 oxide hydrase and BP 4,5 oxide hydrase activities (r= 0.93 to 0.98; p < 0.001). A similar high correlation was observed between BP 4,5 oxide hydrase activity and hydrase activity for BP 7,8 oxide, BP 9,10 oxide and BP 11,12 oxide (r= 0.91 to 0.98; p < 0.001). The results obtained suggest the presence in human liver of either a single hydrase with broad substrate specificity or several epoxide hydrases that are under similar regulatory control.