CHARACTERIZATION OF MICROSOMAL CYTOCHROME-P450 ENZYMES INVOLVED IN THE OXIDATION OF XENOBIOTIC CHEMICALS IN HUMAN FETAL LIVERS AND ADULT LUNGS

Levels and catalytic activities of cytochrome P450 (P450) enzymes invo lved in the oxidation of drugs and carcinogens were determined in huma n adult lungs and fetal livers and compared with those in microsomes f rom adult livers, P450s immunoreactive with anti-human P4501A1 and ant i-human P4503A antibodies were detected in fetal liver microsomes by i mmunoblotting analysis, and P450s related to P4501A1,2A6, 2C9, 2E1, an d 3A4 were determined in adult lung microsomes; all of these P450 enzy mes were detected in much higher amounts in adult liver microsomes exc ept that P4501A2 was only the 1A subfamily of P450 found in adult live rs, Drug oxidation activities with the substrates ethoxyresorufin, cou marin, 7-ethoxycoumarin, bufuralol, and testosterone were determined i n these microsomes, and we found that none of the activities were high er in microsomes of adult lungs and fetal livers than in adult livers. Activation of procarcinogens to reactive metabolites that induce umu gene expression in Salmonella typhimurium TA1535/pSK1002 or NM2009 was also examined and it was found that activities with (+)- and (-)-enan tiomers of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene were higher in feta l liver microsomes than adult lung or liver microsomes. The adult live r and lung activities for these two procarcinogens were similar on the basis of microsomal protein contents despite the fact that P450 conte nts are higher in liver than lung microsomes. alpha-Naphthoflavone, a known inhibitor of P4501A-related activities, did not affect these pro carcinogen activation in fetal liver microsomes. Fetal liver microsome s catalyzed activation of aflatoxin B-1, and sterigmatocystin, two pro carcinogens known to be activated by P4503A4/7 in humans, although act ivation of carcinogenic arylamines that are good substrates for P4501A 2 was much lower in microsomes of fetal livers and adult lungs than in adult livers, These results suggest that in human fetal livers at lea st two P450 enzymes, a form of P450 that is immunoreactive to P4501A1 and P4503A7, are actually expressed and these enzymes are suggested as being involved in the activation of the (+)- and (-)-enantiomers of 7 , 8-dihydroxy-7, 8-dihydrobenzo[a]pyrene and the carcinogenic mycotoxi ns, respectively. The exact nature of the former enzyme in fetal liver s is unknown, In adult human lungs, several P450 enzymes are expressed , although the precise roles of these enzymes in the oxidation of xeno biotics were not determined due to the low level of expression of thes e P450s.