Metabolism of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and glutathione conjugates in isolated rat hepatocytes.
Isolated hepatocytes from 3-methylcholanthrene (MC)-treated rats metabolized trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) to water soluble conjugates including glutathione (GSH) conjugates. Under the conditions employed 35% of total water soluble products derived from BP-7,8-diol could be accounted for by GSH conjugates. The corresponding figure for anti-BPDE was estimated to be greater than or equal to 80%. Isolated hepatocytes metabolized BP-7,8-diol and anti-BPDE to GSH conjugates at maximal rates of 0.5 and 9 nmol per 10(6) cells per min, respectively. Thus, identifying the rate limiting step in the reaction sequence as the metabolism of BP-7,8-diol to the GSH conjugating intermediates. In addition to the direct conjugation of anti-BPDE with GSH, anti-BPDE but not the corresponding BP-tetraols, was further metabolized to reactive intermediates that subsequently bound to cellular proteins or reacted with GSH forming water soluble conjugates. The identity or identities of these novel reactive intermediates is discussed.
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004101:Dihydroxydihydrobenzopyrenes; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D008298:Maleates / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence
D001571:Benzoflavones; D001580:Benzopyrenes; D004101:Dihydroxydihydrobenzopyrenes; D046911:Macromolecular Substances; D008298:Maleates; D011506:Proteins; C017228:benzo(a)pyrene 7,8-dihydrodiol; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C011512:alpha-naphthoflavone; C014476:diethyl maleate; D005978:Glutathione