Biotransformation of trans-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene to benzo[a]pyrene bis-diols and DNA adducts by induced rat liver microsomes.
The biotransformation of (+/-)-trans-4,5-dihydroxy-4, 5-dihydrobenzo[a]pyrene (trans-B[a]P-4,5-diol), the K-region dihydrodiol of B[a]P, by beta-naphthoflavone (BNF)-induced rat liver microsomes was studied. trans-B[a]P-4,5-diol was metabolized to six major products as characterized by NMR, MS, and UV spectroscopy, and all were identified as bis-diols: two diastereomers of trans,trans-4, 5:7,8-tetrahydroxy-4,5:7,8-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:7,8-bis-diol), two diastereomers of trans,trans-4, 5:9,10-tetrahydroxy-4,5:9,10-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:9,10-bis-diol), and two diastereomers of the somewhat unusual trans,trans-1,2:4,5-tetrahydroxy-1,2:4, 5-tetrahydrobenzo[a]pyrene (trans,trans-B[a]P-1,2:4,5-bis-diol). BNF-induced rat liver microsomes also metabolized B[a]P to the same trans-B[a]P-4,5-diol-derived bis-diols. The ability of trans-B[a]P-4, 5-diol to form DNA adducts was investigated using (32)P-postlabeling techniques specifically designed to detect stable polar DNA adducts. Four DNA adducts were detected after microsomal activation of trans-B[a]P-4,5-diol with calf thymus DNA. Further analyses indicated that each of these stable polar DNA adducts was derived from the further metabolic activation of the trans,trans-B[a]P-4,5:7, 8-bis-diols. We conclude that trans-B[a]P-4,5-diol can be metabolized to a series of B[a]P-bis-diols, and can also be metabolically activated to form stable polar DNA adducts. The trans, trans-B[a]P-4,5:7,8-bis-diols were shown to be metabolic intermediates in the formation of these DNA adducts.
Padgett
W T
WT
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, MD-68, Research Triangle Park, North Carolina 27711, USA.
Davis
C
C
Lambert
G
G
Nelson
G B
GB
Ross
J A
JA
Yacopucci
M
M
Nesnow
S
S
D000818:Animals; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis*; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002273:Carcinogens; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; C015813:4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene; D001564:Benzo(a)pyrene; D019324:beta-Naphthoflavone; D004247:DNA