,2-dihydroxybenzene (catechol), an abundant phenolic constituent of igarette smoke and coffee, is a strong cocarcinogen and co-initiator with enzo[a]pyrene (BaP) in mouse skin. Our studies on the effects of catechol n metabolism and DNA adduct formation by BaP in mouse skin have shown that atechol (1) increases the ratio of anti- to syn-7,8-dihydroxy-9,10- etrahydroBaP (BPDE); (2) increases the ratio of anti- to syn BPDE-DNA dducts; (3) suppresses glucuronide and sulfate conjugation of BaP etabolites; (4) enhances the formation of unconjugated 3-hydroxy-BaP (BaP- -OH). These results suggest that catechol may be involved in peroxide- ependent free redical processes and generates hydroxyl (OH) radicals. In he present proposal we will extend our research as follows: (1) Investigate he above hypothesis by (a); quantitating modification of prelabelled hymine residues of mouse skin DNA to cis-5,6-dihydroxy-5,6-dihydrothymine nd 5-hydroxymethyluracil, and modification of deoxyguanosine residues to 8- ydroxyguanine by postlabelling techniques (b); quantitating formation of he two enantiomers of trans-[BaP]7,8-dihydroxy-7,8-dihydroBaP (BaP-7,8- iol) 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) nvestigate the mechanism of glucuronide conjugation by studying the etabolism of {3H] catechol in the presence and absence of BaP, the etabolims of [3H]BaP-3-OH in the presence and absence of catechol, and the ffect of catechol on beta-glucuronidase and glucuronosyltransferase ctivities in mouse skin. (3) Investigate the association of the observed ncreases in the levels of anti-BPDE or BaP-3-OH with the biological ctivity of catechol by determining the co-initiating activity of catechol ith the enantiomers of BaP-7,8diol and with BaP-3-OH in mouse skin. he goal of these studies is to understand the mechanism(s) of action of atechol as a cocarcinogen with BaP, and to assess the possible role of atechol in human cancer etiology.
NIH ExPorter
NIH ExPorter