Metabolic Activation of Procarcinogens by Human Cytochrome P450 Enzymes in Microsomes of Adult and Fetal Livers and of Adult Lungs

Abstract

Levels and catalytic activities of cytochrome P450 (P450) enzymes involved in the oxidation of drugs and carcinogens were determined in human adult lungs and fetal livers and compared with those in microsomes from adult livers. P450s immunoreactive with anti-human P450 1A1 and anti-human P450 3A antibodies were detected in fetal liver microsomes by immunoblotting analysis, and P450s related to P450 1A1, 2A6, 2C9, 2E 1, and 3A4 were determined in adult lung microsomes; all of these P450 enzymes were detected in much higher amounts in adult liver microsomes except that P450 1A2 was only the 1A subfamily of P450 found in adults. Drug oxidation activities with several substrates were determined in these microsomes, and we found that none of the activities were higher in microsomes of adult lungs and fetal livers than in adult livers. Activation of procarcinogens by P450 enzymes was also examined and it was found that activities with (+)- and (-)-enantiomers of 7, 8-dihydroxy-7, 8-dihydrobenzo[a]pyrene were higher in fetal liver microsomes than adult lung or liver microsomes. Anti-human P450 1A1 and 1A2 and a-naphthoflavone, known to inhibit P450 IA-related activities, did not affect these procarcinogen activation in fetal liver microsomes. Fetal liver microsomes catalyzed activation of aflatoxin B₁ and sterigmatocystin, although activation of carcinogenic arylamines was much lower in microsomes of fetal livers and adult lungs than of adult livers. These results suggest that in human fetal livers at least two P450 enzymes, namely P450 IA-related enzyme and P450 3A7, are actually expressed and these enzymes are involved in the activation of the (+)- and (-)-enantiomers of 7, 8-dihydroxy-7, 8-dihydrobenzo[a]pyrene and the carcinogenic mycotoxins, respectively. In adult human lungs, several P450 enzymes are expressed, though the precise roles of these enzymes in the oxidation of xenobiotics were not determined due to the low level of expression of these P450s.