Non-arene oxide aromatic ring hydroxylation of 2,2',5,5'-tetrachlorobiphenyl as the major metabolic pathway catalyzed by phenobarbital-induced rat liver microsomes.

Incubation of phenobarbital-induced rat liver microsomes with 2,2',5,5'-tetrachlorobiphenyl (TCB) yielded about 30% of the substrate as 3-hydroxy-TCB, 3,4-dihydroxy-TCB, 3,3'-dihydroxy-TCB (tentative identification), and 3,4-dihydro-3,4-dihydroxy-TCB in relative amounts of about 1:1:0.05:0.05. Under identical conditions, 2,2',5,5'-tetrachlorobiphenyl 3,4-oxide (TCBO) yielded about 45% of the substrate as the above products in an approximate ratio of 0.1:1:0.01:1, as well as 10% as TCB. Omission of NADPH from incubations of TCBO decreased the yields of 3-hydroxy-TCB, both dihydroxy-TCBs, and TCB by 75-100%, increased the yield of 3,4-dihydro-3,4-dihydroxy-TCB 4-fold, and permitted the recovery of small amounts (0.5% yield) of 4-hydroxy-TCB. 3-Hydroxy-TCB and 4-hydroxy-TCB were both extensively metabolized to 3,4-dihydroxy-TCB; 3-hydroxy-TCB was also metabolized to the presumed 3,3'-dihydroxy-TCB. The metabolism of TCBO to 3,4-dihydro-3,4-dihydroxy-TCB was inhibited by 1,1,1-trichloropropene 2,3-oxide. These data indicate that the majority (greater than 90%) of the primary oxidation of TCB occurred via 3-hydroxylation mechanisms not involving TCBO and that only a small fraction occurred via 3,4-epoxidation. The formation of 3-hydroxy-TCB and TCBO from TCB via different pathways was consistent with the observation that TCB-treated rats excreted 6-fold higher levels of 3-hydroxy-TCB in their feces than did TCBO-treated rats.