[Metabolism of 2, 3', 4, 4', 5-pentachlorobiphenyl in guinea pig microsomes]

The in vitro metabolism of 2,3',4,4',5-pentachlorobiphenyl (pentaCB) (CB118) was studied using liver microsomes of guinea pigs and the effect of cytochrome P450 inducers, phenobarbital (PB) and 3-methylcholanthrene (MC) on CB118 metabolism was also compared. After 30 min-incubation at 37 degrees C with liver microsomes of guinea pigs, CB118 was hydroxylated to two metabolites (M(-1) and M(-2)) with retention times of 15.84 min and 20.01 min in GC/ECD, respectively. GC/MS showed that the methylated derivative of a major metabolite M(-2) had the molecular weight of 354 and an intense fragment ion of [M(+)-50] which is a characteristic ion for PCBs possessing a methoxy-group at the 2 (2')- or the 6 (6')-position. By comparison of the mass fragmentation and the retention times in GC/MS with the synthetic authentic compounds, M(-2) was identified as 2-hydroxy-3,3',4,4',5-pentaCB (CB126). On the other hand, the methylated derivative of a minor metabolite M(-1) had the molecular weight of 320 and the similar fragment ion of [M(+)-50] to the methylated M(-2), assuming that M(-1) was a dechlorinated monohydroxy-tetrachlorobiphenyl (tetraCB) possessing hydroxy-group at the 2 (2')- or the 6 (6')-position. However, the precise structure of M-1 could not be determined because its retention time in GC was in disagreement with that of the candidate 6-hydroxy-3,3',4,4'-tetraCB. PB-treatment increased the formation of M(-1) and M(-2) to 2.2- and 6.8-fold of untreated animals, whereas MC-treatment increased only M(-2) to 2.6-fold of untreated ones. Addition of antiserum against a PB-inducible guinea pig cytochrome P450, CYP2B18, completely inhibited the formation of M(-2). These results suggest that CB118 is principally metabolized by CYP2B18 to 2-hydroxy-CB126 which is formed via a 2,3-epoxide intermediate and the subsequent NIH-shift of a chlorine at the 2-position to the 3-position in guinea pig liver.