1,2-dihydroxybenzene (catechol), an abundant phenolic constituent of cigarette smoke and coffee, is a strong cocarcinogen and co-initiator with benzo[a]pyrene (BaP) in mouse skin. Our studies on the effects of catechol in metabolism and DNA adduct formation by BaP in mouse skin have shown that catechol (1) increases the ratio of anti- to syn-7,8-dihydroxy-9,10- tetrahydroBaP (BPDE); (2) increases the ratio of anti- to syn BPDE-DNA adducts; (3) suppresses glucuronide and sulfate conjugation of BaP metabolites; (4) enhances the formation of unconjugated 3-hydroxy-BaP (BaP- -OH). These results suggest that catechol may be involved in peroxide- dependent free redical processes and generates hydroxyl (OH) radicals. In the present proposal we will extend our research as follows: (1) Investigate the above hypothesis by (a); quantitating modification of prelabelled thymine residues of mouse skin DNA to cis-5,6-dihydroxy-5,6-dihydrothymine and 5-hydroxymethyluracil, and modification of deoxyguanosine residues to 8- hydroxyguanine by postlabelling techniques (b); quantitating formation of the two enantiomers of trans-[BaP]7,8-dihydroxy-7,8-dihydroBaP (BaP-7,8- diol) from BaP; and (c); quantitating formation of the 4 enantiomers of syn- and anti BPDE from (+) or (-) [3H]BaP-7,8-diol in mouse skin. (2) investigate the mechanism of glucuronide conjugation by studying the metabolism of {3H] catechol in the presence and absence of BaP, the metabolims of [3H]BaP-3-OH in the presence and absence of catechol, and the effect of catechol on beta-glucuronidase and glucuronosyltransferase activities in mouse skin. (3) Investigate the association of the observed increases in the levels of anti-BPDE or BaP-3-OH with the biological activity of catechol by determining the co-initiating activity of catechol with the enantiomers of BaP-7,8diol and with BaP-3-OH in mouse skin. The goal of these studies is to understand the mechanism(s) of action of catechol as a cocarcinogen with BaP, and to assess the possible role of catechol in human cancer etiology.
