Metabolic Activation of Racemic and Enantiomeric trans-8,9-Dihydroxy-8,9-dihydrodibenzo[a,l]pyrene (Dibenzo[def,p]chrysene) to Dibenzo[a,l]pyrene-bis-d

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• 作者：Stephen Nesnow ; Christine Davis ; William Padgett ; Michael George ; Guy Lambert ; Fabienne Meyers ; Joycelyn Allison ; Linda Adams ; and Leon C. King
• 刊名：Chemical Research in Toxicology
• 出版年：1998
• 出版时间：December 1998
• 年：1998
• 卷：11
• 期：12
• 页码：1596 - 1607
• 全文大小：147K
• 年卷期：v.11,no.12(December 1998)
• ISSN：1520-5010

文摘

Metabolic activation studies of dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene), anextremely potent environmental carcinogen, have been focused on metabolism at the fjordregion, a region associated with high mutagenic and carcinogenic activities of the correspondingfjord-region DB[a,l]P-11,12-diol-13,14-epoxides. DB[a,l]P is metabolized by chars/beta2.gif" BORDER=0 ALIGN="middle">-naphthoflavone(BNF)- and 3-methylcholanthrene-induced rat liver microsomes and a recombinant humanP450 1A1 system to two major dihydrodiols, the K-region dihydrodiol, DB[a,l]P-8,9-dihydrodiol(DB[a,l]P-8,9-diol), and the fjord-region dihydrodiol, DB[a,l]P-11,12-dihydrodiol. We haveinvestigated the further metabolic activation of DB[a,l]P-8,9-diol by BNF-induced rat livermicrosomes and a recombinant human P450 1A1 system with epoxide hydrolase to DB[a,l]P-bis-diols and to DNA adducts. (±)-trans-DB[a,l]P-8,9-diol was synthesized and resolved intoits enantiomers. Racemic trans-DB[a,l]P-8,9-diol was metabolized by BNF-induced rat livermicrosomes to six metabolites: two diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol,two diastereomers of trans,cis-DB[a,l]P-8,9:11,12-bis-diol, and two diastereomers of trans-DB[a,l]P-8,9:13,14-bis-diol as characterized by NMR, MS, and UV spectroscopy. Metabolic studiesusing both enantiomeric (-)- and (+)-trans-DB[a,l]P-8,9-diol further demonstrated that eachdiastereomer of trans,trans-DB[a,l]P-8,9:11,12-bis-diol and trans-DB[a,l]P-8,9:13,14-bis-diol wascomprised of two enantiomers. Similarly, incubations of enantiomeric or racemic trans-DB[a,l]P-8,9-diol with a recombinant human P450 1A1 system and epoxide hydrolase also gavethe same two enantiomeric mixtures of diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol and the same two enantiomeric mixtures of diastereomers of trans-DB[a,l]P-8,9:13,14-bis-diol. This suggested that the microsomal oxidations of (-)- and (+)-trans-DB[a,l]P-8,9-diolwere stereospecific. The stereospecific formation of enantiomers of trans-DB[a,l]P-8,9-diol fromDB[a,l]P was examined using both BNF-induced rat liver microsomes and a recombinant humanP450 1A1 system with epoxide hydrolase. Stereospecificity was observed as both metabolicsystems favored the formation of (-)-trans-DB[a,l]P-8,9-diol by 8-9-fold. DNA adduct studieswere undertaken using TLC/HPLC ³²P-postlabeling techniques. In the presence of a recombinant human P450 1A1 system with epoxide hydrolase, DB[a,l]P gave two groups of calfthymus DNA adducts. The group of later-eluting adducts were identified as arising from syn-and anti-DB[a,l]P-11,12-diol-13,14-epoxides, while the more polar early-eluting adducts werederived, in part, from the further activation of trans-DB[a,l]P-8,9-diol. Our data indicate that,in P450 1A1-mediated microsomal incubations, DB[a,l]P is metabolized to trans-DB[a,l]P-8,9-diol which is further metabolized to DB[a,l]P-bis-diols. trans-DB[a,l]P-8,9-diol is metabolicallyactivated to intermediates that can bind to DNA and give DNA adducts similar to thoseobserved with DB[a,l]P. These results indicate that DB[a,l]P can be metabolically activatedby both fjord-region and K-region pathways.