1 research outputs found
Oxidation of Polychlorinated Biphenyls by Liver Tissue Slices from Phenobarbital-Pretreated Mice Is Congener-Specific and Atropselective
Mouse models are powerful tools to
study the developmental neurotoxicity
of polychlorinated biphenyls (PCBs); however, studies of the oxidation
of chiral PCB congeners to potentially neurotoxic hydroxylated metabolites
(OH-PCBs) in mice have not been reported. Here, we investigate the
atropselective oxidation of chiral PCB 91 (2,2′,3,4′,6-pentachlorobiphenyl),
PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), PCB 132 (2,2′,3,3′,4,6′-hexachlorobiphenyl),
PCB 136 (2,2′,3,3′,6,6′-hexachlorobiphenyl),
and PCB 149 (2,2′,3,4′,5′,6-hexachlorobiphenyl)
to OH-PCBs in liver tissue slices prepared from female mice. The metabolite
profile of PCB 136 typically followed the rank order 5-OH-PCB >
4-OH-PCB
> 4,5-OH-PCB, and metabolite levels increased with PCB concentration
and incubation time. A similar OH-PCB profile was observed with the
other PCB congeners, with 5-OH-PCB/4-OH-PCB ratios ranging from 2
to 12. More 5-OH-PCB 136 was formed in liver tissue slices obtained
from animals pretreated with phenobarbital (P450 2B inducer) or, to
a lesser extent, dexamethasone (P450 2B and 3A enzyme inducer) compared
to tissue slices prepared from vehicle-pretreated animals. The apparent
rate of 5-OH-PCBs formation followed the approximate rank order PCB
149 > PCB 91 > PCB 132 ∼ PCB 136 > PCB 95. Atropselective
gas
chromatography revealed a congener-specific atropisomeric enrichment
of major OH-PCB metabolites. Comparison of our results with published
OH-PCB patterns and chiral signatures (i.e., the direction and extent
of the atropisomeric enrichment) from rat liver microsomal revealed
drastic differences between both species, especially following the
induction of P450 2B enzymes. These species differences in the metabolism
of chiral PCBs should be considered in developmental neurotoxicity
studies of PCBs