Transformation of normal hamster cells by benzo(a)pyrene diol‐epoxide

Abstract

The frequency of cell transformation was determined after treatment of normal hamster embryo cells with benzo(a)pyrene (BP) and six of its metabolites. These metabolites included the trans 4,5-, 7,8- and 9,10-dihydrodiols; the 4,5-epoxide; and two stereoisomers of the non-K-region diol epoxides r-7, t-8-dihydroxy t-9, 10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1) and r-7, t-8, dihydroxy c-9, 10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 11). The trans 7,8-dihydrodiol was more active than the other two dihydrodiols tested and was also more active than the parent hydrocrabon BP. Of the three epoxides tested, the diol-epoxide 1 was more active than the 4,5-epoxide and diol-epoxide 11. The results suggest that diol-epoxide 1 is a major cell-transforming metabolite of BP.

Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes

“…A likely source of dermal contact with toxic BaP levels would be in petroleum industry workers. Bioactivated BaP is a potent skin carcinogen (Mager et al, 1977). When applied dermally, BaP induces cytokinetic abnormalities and inflammation, followed by skin tumors (Albert et al, 1996;Lee and O'Neill, 1971).…”

Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes.

“…The water-soluble products formed by cells (64, 310), although chemically uncharacteritied, are likely to be either sulfate, glutathione, or glucuronide conjugates. Some of these reactions form metabolic intermediates that bind convalently to DNA and RNA (3,11-15, 29,33,34,53,59,61,67,77,80,81,84,94,96,130-133,137-139,142,143, 159, 165-168,172,201-203,212,235,239,242,247,249-252,274,278,283,286, 291, [300][301][302]331) and have a variety of biological activities that include cytotoxicity (183,317,318,323), mutagenicity (5, 68, 119-121, 124, 125, 187, 188, 190-193, 196,209,210, 225,226, 254,279, 280,317,323), cell transformation in vitro (41,119,184,(192)(193)(194)(195), and cancer induction in experimental animals (36, 44,84,146,148,163,[175][176][177][178].…”

Interactions of Molecules with Nucleic Acids. X. Covalent Intercalat e Binding of the Carcinogenic BPDE I(+) to Kinked DNA

“…(lS-17) Covalently bound adducts have entailed reaction of diol-epoxides of PAHs with amino groups of guanine, cytosine and adenine. (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(18)(19)(20)(21)(22)(23)(24) In addition, covalent bond formation to the N7 ring nitrogen in guanine with ring opening and strand sission, and phosphorylation are two other reaction processes which have been identified. (6,25,26) However, the analysis of adducts to DNA with HPLC tech-884 Taylor, 8/eyer & Miller niques entails hydrolysis with a subsequent loss of all but the BPDE bonded to the amino nitrogen of one of the bases, thereby focusing attention on these.…”

“…(2,6,8,9) Binding to N2 on guanine is most prevalent, and this has received much attention. (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(18)(19)(20)(21) Of particular interest is the structure of this BPDE I(+) adduct to DNA. To date, no crystal structure has been reported.…”

“…and covalently bound adducts with DNA. (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) The arene oxides are among the most reactive, and it is assumed that their reaction with cellular macromolecules is a critical step in the carcinogenic event. (lS-17) Covalently bound adducts have entailed reaction of diol-epoxides of PAHs with amino groups of guanine, cytosine and adenine.…”