Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes

Detection and measurement of the agonistic activities of PCBs and mono-hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay

“…Non-dioxin-like PCBs 99, 153, 180 and 194 but not a dioxin-like coplanar PCB 77, all at 10 lM, significantly activated the human CAR in Huf7 human hepatocellular carcinoma cells transfected with an expression plasmid for the receptor (Al-Salman and Plant, 2012). In addition, non-dioxin-like PCBs 28, 52, 101, 138, 153 and 180, at concentrations of 5 lM or lower, induced CYP2B1 mRNA in primary rat hepatocytes after 24 h of incubation (Gährs et al, 2013). All PCBs used in the present study were non-dioxin-like (including a non-dioxin-like coplanar PCB 12).…”

“…Indeed, there are reports that several non-coplanar PCBs (rather than the coplanar PCBs known to be highly toxic) directly activate CAR and PXR and increase transcription of genes for CYP2B and CYP3A (Al-Salman and Plant, 2012;Gährs et al, 2013). However, the CAR/PXR agonistic properties of PCBs are a new subject for investigation and it is not known how metabolism of PCBs changes their abilities to interact with the CAR/PXR.…”

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

“…Recently, pronounced CAR activation along with minor effects on the pregnane-X-receptor (PXR) were reported in rat hepatocytes treated with various NDL-PCBs, including PCB 180 [43]. Lack of the typical AHR dependent responses on hepatic CYP1A1 induction [17], thymus weight and histology, as well as body weight development confirm that PCB 180 lacks several of the specific effects required for assignment of a toxic equivalency factor (TEF) for DL compounds according to the WHO [44].…”

PCB-associated steatohepatitis and the role of nuclear receptors.

“…Far from being inert, the remaining 98.5% of this mixture contains congeners which are known to induce other receptors, including both classical xenobiotic nuclear receptors 19,[33][34][35] and cell surface receptors…”

“…The distribution of congeners found in the adipose tissue and serum of humans contains species which are known to modulate the activity of AhR, PXR, CAR 19,34,35,155 and other receptors, and may, through crosstalking pathways, affect the transcriptional function of LXR. Because each of these receptors modulates gene targets related to steatohepatitis, an understanding of the contribution of each of these transcription factors to the overall PCB-modified transcriptome would assist with both risk assessment and the rational development of therapies.…”