R 01.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptWu etR 01.NIH-PA Author Manuscript NIH-PA

R 01.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptWu et
R 01.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptWu et al.Page2011), was enriched in liver tissue slices. Equivalent enrichment patterns have been observed in DOT1L Purity & Documentation research applying rat liver microsomes and in vivo results (Kania-Korwel et al., 2008b; Wu et al., 2011). Interestingly, the extent and direction on the enantiomeric enrichment of each OHPCBs was independent with the Cathepsin K Gene ID inducer pretreatment and also the sex. By far the most intriguing observations in the present study will be the sex-specific differences within the OH-PCB profiles and levels observed with traditional and enantioselective gas chromatographic analysis. Especially, OH-PCB levels had been greater in liver slices obtained from male versus female rats, independent in the inducer therapy. The greater OH-PCB levels in liver slices from male rats are likely due to higher CYP2B activities in male in comparison with female rats. Because tissue slices are a very good model to predict sex-specific differences in xenobiotic metabolism (Ohyama et al., 2005a; Ohyama et al., 2005b), our findings suggest that male rats eradicate PCB 136 much more swiftly than female rats, both in CTL animals and just after induction of P450 enzymes. Towards the greatest of our understanding, sex distinct differences in the toxicokinetics of PCB congeners metabolized within the rat haven’t been studied to date. Our observations raise the question of regardless of whether differences in hepatic CYP2B activity lead to distinct profiles and levels of neurotoxic PCB atropisomers and their metabolites in the target site throughout developmentally sensitive periods. Such differences in toxicant levels could play a role in PCBs’ developmental neurotoxicity and contribute to the sex-specific variations observed in developmental toxicity studies in rats (Roegge et al., 2000; Widholm et al., 2001). Given that CYP2B6, the human orthologue of rat CYP2B1, is an inducible enzyme (Zanger et al., 2007), our findings also indicate that the susceptibility to neurodevelopmental effects of PCBs may possibly be modulated by the very variable activity of CYP2B6 in humans. Although it really is nevertheless unclear to what extent sex influences the expression of CYP2B6 (Zanger et al., 2007), further research are warranted to investigate a potential role of hepatic PCB metabolism by CYP2B6 within the sex precise neurodevelopmental effects following PCB exposure in humans. While PCB 136 was associated with hippocampal tissue slices, OH-PCB 136 metabolites levels in hippocampal slice cultures were below background levels, which may well reflect the low constitutive expression of CYP2B1/2 enzymes in mammalian brains (Volk et al., 1995) or, similar to liver tissue slice cultures (Hashemi et al., 2000), the loss of P450 enzyme activity with incubation time. To date, OH-PCBs happen to be detected inside the brain of cetaceans (Kunisue et al., 2007), polar bears (Gebbink et al., 2008) and rats (Meerts et al., 2002), whereas OH-PCB levels were below the detection limits in mice exposed subchronically to PCB 95 (Kania-Korwel et al., 2012). The OH-PCBs inside the brain are generally reduced than in liver mainly because OH-PCBs are far more protein than lipid connected (Gebbink et al., 2008). General, extra studies using much more sensitive analytical tools are needed to investigate levels and enantiomeric enrichment of chiral OH-PCBs in brain.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptConclusionsThe present study demonstrates that each sex along with the induction of P450 enzyme influence the metabolism of PCB 136 atropisomer.