Four Forms of Cytochrome P‐450 in Human Fetal Liver: Purification and Their Capacity to Activate Promutagens

Abstract

Four forms of cytochrome P‐450 were separated and purified to electrophoretic homogeneity from human fetal livers. These forms of cytochrome P‐450, termed P‐450HFLa, P‐450HFLb, P‐450HFLc and P‐450HFLd, were distinguishable from each other in their molecular weights, spectral properties, immunochemical properties and mutagen‐producing activities from promntagens. The molecular weights of P‐450HFLa, b, c and d were estimated to be 51,500, 49,000, 51,500 and 50,000, respectively. Antibodies to P‐450HFLa recognized P‐450HFLc but not P‐450HFLb or d, and antibodies to rat P‐448‐H (P‐450IA2) cross‐reacted with P‐450HFLb but not with other forms of cytochrome P‐450. The N‐terminal amino acid sequence of P‐450HFLc was highly homologous, but not identical, to that of P‐450HFLa. Each form of cytochrome P‐450 catalyzed mutagenic activation of aflatoxin Bl (AFB1), 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ) and 2‐amino‐6‐methyldipyrido‐[l,2‐a:3′,2′‐d]imidazole (Glu‐P‐1) at different rates. P‐450 HFLa showed activities to produce mutagen(s) from AFB1, IQ and to a lesser extent from Glu‐P‐1. P‐450 HFLb activated IQ at a faster rate than did the other forms. P‐450 HFLc produced a mutagen from AFB1 and Glu‐P‐1 but not from IQ. P‐450 HFLd did not activate these promutagens at significant rates.

Effects of age increase on hepatic expression and activity of cytochrome P450 in male C57BL/6 mice

“…Substantial evidence suggests that human CYP1A1 is constitutively expressed very early in development, but not at appreciable levels in adult liver (Kitada et al 1991). Omiecinski et al (1990) reported that CYP1A1 mRNA is expressed constitutively in the rat as early as day 15 of fetal liver development.…”

Heterocyclic amines: Chemistry and health

“…Numerous studies converge on the recognition of cytochrome P450 1A2 as the most important phase I oxygenase for conversion of these aromatic amines to their corresponding hydroxylamines [136][137][138][139]. However, contribution by other cytochromes P450 should by no means be neglected when assessing the total risk [119,132,137,[140][141][142][143][144][145][146]. Four mammalian phase II enzymes have been identified, N-acetyltransferase (NAT), sulfotransferease, prolyl tRNA synthetase, and phosphorylase which produce N-acetoxy, N-sulfonyloxy, N-prolyloxy, and N-phosphatyl ester derivatives, respectively [117,120,122,130,138,147,148].…”

Do Cytochrome P450 Enzymes Contribute to the Metabolism of Xenobiotics in Human?

“…The metabolism of a number of organophoshate and pyrethroid insecticides has been reported to be mediated by CYP3A5 (Mutch & Williams, 2006;Mutch et al, 2003;Godin et al, 2007). CYP3A7 has similar catalytic properties compared with other CYP3A enzymes, including testosterone 6 -hydroxylation (Kitada et al, 1985;Kitada et al, 1987;Kitada et al, 1991).…”