Catechol-induced alterations in metabolic activation and binding of enantiomeric and racemic 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrenes to DNA in mouse skin.
Catechol (1,2-dihydroxybenzene) is a potent co-carcinogen with benzo[a]pyrene (BaP) and with (+/-)-7,8-dihydroxy-7,8- dihydrobenzo[a]pyrene (BaP-7,8-diol) in mouse skin. The effects of catechol on the metabolic activation of (+)- and (-)-[3H]BaP-7,8-diols and on epidermal DNA adduct formation of racemic and enantiomeric [3H]BaP-7,8-diols were examined by applying the tritiated diols to mouse skin. The major metabolite of the (+)-[3H]BaP-7,8-diol was the hydrolysis product of (-)-[3H]-7 alpha, 8 beta-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE). This suggests that a peroxyl radical-mediated pathway is predominantly responsible for the epoxidation of this diol. Formation of (-)-anti[3H]BPDE from (+)-[3H]BaP-7,8-diol was greater than that of (+)-anti-BPDE from (-)-[3H]BaP-7,8-diol. Co-application of catechol with [3H]BaP-7,8-diols inhibited epoxidation of the (+) enantiomer to a greater extent than that of the (-) enantiomer. Catechol decreased the total DNA-binding and the formation of the major adduct with (+)-[3H]BaP-7,8-diol metabolites but catechol had no significant effect on the binding and formation of (+)-anti-[3H]BPDE-deoxyguanosine, the major DNA adduct derived from (-)-[3H]BaP-7,8-diol. Co-administration of catechol with (+/-)-[3H]BaP-7,8-diol increased the ratio of (-)- to (+)-[3H]BaP-7,8-diol derived major DNA adducts in mouse skin suggesting that catechol selectively inhibits certain pathways of metabolic activation of (+/-)-[3H]BaP-7,8-diol. Thus, catechol modifies the tumorigenic activity of (+/-)-BaP-7,8-diol either by alteration of the relative proportion of various hydrocarbon:DNA adducts or by a totally different as yet unexplored mechanisms.
Melikian
A A
AA
Naylor Dana Institute, American Health Foundation, Valhalla, NY 10595.
Bagheri
K
K
Goldin
B F
BF
Hoffmann
D
D
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002396:Catechols / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D002396:Catechols; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D014316:Tritium; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA; C034221:catechol