2 research outputs found
Microsomal Oxidation of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) Results in Species-Dependent Chiral Signatures of the Hydroxylated Metabolites
Chiral polychlorinated biphenyls
(PCBs) display variable atropisomeric
enrichment in wildlife and animal models, especially at higher trophic
levels. These differences in PCBs’ chiral signatures are, at
least in part, due to species-dependent oxidation of PCBs to hydroxylated
PCB metabolites (OH-PCBs). Here, we investigate the hypothesis that
the cytochrome P450 (P450) enzyme-mediated oxidation of chiral PCBs
results in species-dependent differences in the chiral signatures
of OH-PCBs (i.e., the direction and extent of OH-PCBs’ atropisomeric
enrichment). To investigate this hypothesis, we incubated PCB 136,
a representative chiral PCB, with pooled human liver microsomes (HLMs)
or liver microsomes from male guinea pig, hamster, monkey, mouse,
and rabbit or female dog and determined average profiles and chiral
signatures of the OH-PCBs. 2,2′,3,3′,6,6′-Hexachlorobiphenyl-4-ol
(4–136) was the major metabolite in incubations with HLMs and
monkey and rabbit microsomes. 2,2′,3,3′,6,6′-Hexachlorobiphenyl-5-ol
(5–136) was the major metabolite formed by microsomes from
all other species. Both 4–136 and 5–136 were formed
atropselectively in all microsomal incubations; however, the direction
and extent of the atropisomeric enrichment of both OH-PCB metabolites
showed considerable differences across microsomal preparations obtained
from different species. These differences in OH-PCBs’ atropisomeric
enrichment may not only be toxicologically relevant but may also be
useful to study sources and transport of OH-PCBs in the environment
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