Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent

Abstract

Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized.The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups.In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected.Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs.

Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

“…These observations demonstrate that the metabolism of (+)-PCB 136 to E 2 -5-HO-PCB 136 in microsomal incubations is faster compared to the metabolism of (−)-PCB 136 to E 2 -5-HO-PCB 136. Since 5-HO-PCB 136 is the major metabolite, this observation is consistent with an atropisomeric enrichment of (−)-PCB 136 in in vitro (Lu et al 2013, Wu et al 2013b, Wu et al 2011) and in vivo metabolism studies in rats (Kania-Korwel et al 2008c). …”

“…Incubations of individual, racemic PCB congeners or a mixture of several C-PCBs with rat CYP2B1 show preferential transformation of E 2 -PCB 45, (−)-PCB 84, E 1 -PCB 91, E 2 -PCB 95, (−)-PCB 132, (+)-PCB 136 and (−)-PCB 149. The same direction of atropisomeric enrichment is observed in rat liver microsomal incubations (Kania-Korwel et al 2011, Kania-Korwel and Lehmler 2013, Wu et al 2011) and, for PCB 136, in rat liver tissue slices (Wu et al 2013b). At the same time, the formation of HO-PCB metabolites by rat P450 enzymes is atropselective, thus resulting in an atropisomeric enrichment of the HO-PCBs.…”

“…A convenient nomenclature for PCB metabolites has been proposed by Maervoet et al and, as shown for PCB 136 in Fig 3, will be used throughout this manuscript (Maervoet et al 2004). The oxidation of C-PCBs, in particular those with a 2,3,6-trichloro substitution pattern in one phenyl ring, to HO-PCBs has been studied extensively using recombinant enzymes (Lu et al 2013, Lu and Wong 2011, Waller et al 1999, Warner et al 2009), hepatic microsomes (Kania-Korwel et al 2011, Kania-Korwel and Lehmler 2013, Schnellmann et al 1983, Wu et al 2014, Wu et al 2011), isolated hepatocytes (Vickers et al 1986) and, liver, hippocampus and skin slices (Garner et al 2006, Wu et al 2013a, Wu et al 2013b) obtained from mammalian species. To the best of our knowledge, the oxidation of C-PCBs in non-mammalian species, such as amphibians, fish or avian species, has not been investigated to date.…”

“…Several studies using recombinant P450 enzymes (Lu et al 2013, Warner et al 2009), liver microsomes (Kania-Korwel et al 2011, Kania-Korwel and Lehmler 2013, Wu et al 2014, Wu et al 2011) or liver tissue slices (Wu et al 2013a, Wu et al 2013b) demonstrate that PCBs are atropselectively metabolized to HO-CPBs by P450 enzymes, thus resulting in an atropisomeric enrichment of PCBs and HO-PCBs in the microsomal incubation (Table 2). The atropselective biotransformation of C-PCBs to HO-PCB metabolites by recombinant rat and human cytochrome P450 enzymes has been studies in some detail (Lu et al 2013, Warner et al 2009).…”

“…Several recent metabolism studies demonstrate that the atropselective formation of HO-PCBs is also species dependent (Kania-Korwel et al 2008b, Wu et al 2013a, Wu et al 2014, Wu et al 2013b, Wu et al 2011). For example, both 5-HO-PCB136 and 4-HO-PCB136 are atropselectively formed by liver microsomes from humans, dogs, monkeys, guinea pigs, mice, hamsters and rabbits (Fig.…”