Oxidation of cyclopenta[cd]pyrene by human and mouse liver microsomes and selected cytochrome P450 enzymes.
The metabolism of the environmental pollutant and suspected human carcinogen, cyclopenta[cd]pyrene (CPP), was investigated. Human liver microsomes from three individuals were examined, as well as CD-1 mouse liver microsomes. Five new metabolites recently identified in our lab, 4-hydroxy-3,4-dihydroCPP, 3,4-dihydroCPP-cis-3,4-diol, 4-oxo-3,4-dihydroCPP, 3,4,9,10-tetrahydroCPP-trans-3,4-trans-9,10-tetrol, and trans-3,4-dihydroCPP-3, 4,x-triols, as well as the known major metabolite, 3,4-dihydroCPP-trans-3,4-diol, were all observed from the incubations of human liver microsomes and CPP. Even though all three human samples were capable of producing all the metabolites identified from the mouse liver microsomal incubations of CPP, the quantity of each metabolite varied among the microsomal samples. In an attempt to explain the variation among human liver samples, the microsomes derived from genetically engineered cells containing specific cytochrome P450 isozyme cDNAs were employed. It was found that the 3,4-cyclopenta double bond can be oxidized by the cytochrome P450 enzymes 1A1, 1A2, and 3A4. The 9,10 K-region double bond was not efficiently oxidized by cytochrome P450 1A1, but by P450 1A2 either from CPP or from the t-3,4-dihydrodiol. The lack of catalytic activity of 3A4 toward the t-3,4-dihydrodiol, despite its high activity toward CPP oxidation to tetrahydrotetrols, suggests the possibility of two dihydrodiol epoxides, 3,4-dihydrodiol 9,10-epoxide and 9,10-dihydrodiol 3,4-epoxide, of CPP.
Kwon
H
H
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139-4307.
Sahali
Y
Y
Skipper
P L
PL
Tannenbaum
S R
SR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D010084:Oxidation-Reduction; D011721:Pyrenes / Q000378:metabolism*
D009153:Mutagens; D011721:Pyrenes; C016328:cyclopenta(c,d)pyrene; D003577:Cytochrome P-450 Enzyme System