Microsomal metabolism of cyclopenta[cd]pyrene. Characterization of new metabolites and their mechanism of formation.
Oxidation of cyclopenta[cd]pyrene (CPP) by mouse and human liver microsomes was used to produce several previously undescribed metabolites, which were separated and isolated by reversed-phase HPLC. Three of these, 3,4-dihydroCPP-c-3,4-diol, 4-hydroxy-3,4-dihydroCPP, and 4-oxo-3,4-dihydroCPP, were fully characterized by GC-MS and UV spectroscopic analysis as well as by total synthesis. Two additional pairs of metabolites were identified as isomeric tetrahydrotetrols and dihydrotriols by GC-MS analysis of their trimethylsilyl derivatives. Their UV spectra were recorded and found to agree with the structure assignments. The tetrahydrotetrols were further characterized by the fact that either 3,4- or 9,10-trans-dihydrodiol could serve as their precursor, indicating that they are the two diastomeric 3,4,9,10-tetrahydroCPP-t-3,4-t-9,10-tetrols. The dihydrotriols were shown to possess t-3,4-dihydrodiol functionality. As found previously using rat liver microsomes, the most abundant metabolite was 3,4-dihydroCPP-t-3,4-diol. It was produced with one enantiomer in severalfold excess over the other, and the major enantiomer was shown to have 3R,4R configuration by exciton chirality circular dichroism. Microsomal oxidation of [4-2H]CPP, which was synthesized for this study, was used to determine the mechanisms of formation of 4-oxo- and 4-hydroxy-3,4-dihydroCPP. The ketone was produced without detectable retention of deuterium label, eliminating the NIH shift as a possible mechanism. The alcohol was shown to arise by NADPH-dependent reduction of both the ketone and another intermediate presumed to be the 3,4-epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)
Sahali
Y
Y
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Kwon
H
H
Skipper
P L
PL
Tannenbaum
S R
SR
D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011721:Pyrenes / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D002273:Carcinogens; D009153:Mutagens; D011721:Pyrenes; C016328:cyclopenta(c,d)pyrene; D009249:NADP