API

Stressor: 251

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TCPOBOP

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Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat

There is no evidence text for this AOP




Event Evidence

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Activation, Constitutive androstane receptor

There is no evidence text for this event.



Altered gene expression specific to CAR activation, Hepatocytes

TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene)

1.         Hepatic CAR-dependent genes were identified by comparing the gene expression profiles of wild-type and CAR/PXR single and double-knockout mice after intraperitoneal (i.p.)  injection with TCPOBOP and/or  PCN (pregnenolone 16alpha-carbonitrile; PXR activator) for 12 h prior to sacrifice (3 mg/kg body weight) (Tojima et al., 2012). Both common and unique gene target genes for CAR and PXR were identified. CAR-dependent gene targets included those involved in xenobiotic metabolism, apoptosis, cholesterol metabolism and lipid metabolism. A similar experiment in wild-type C57BL/6N mice administered TCPOBOP (i.p., 3 mg/kg) or PCN once daily for four days identified common and unique CAR- and PXR-target genes (Cui and Klaassen, 2016).

2.         The hepatic gene expression profiles of CAR-null, PXR-null, and PXR/CAR-null and WT rats after single treatment (i.p.; 16 h after injection) with vehicle (corn oil), PXR agonist PCN (100 mg/kg) and/or TCPOBOP (12.5 mg/kg) were compared. The results identified that PXR and CAR are involved in the regulation and expression of both common and different drug metabolizing genes in the rat liver (Forbes et al., 2017). As an example, induction of rat Cyp2b2 expression was avidly expressed in wild-type and PXR-null rats, but was blocked in the CAR-null and PXR/CAR-null rats.

3.         Comparison of gene expression profiles of wild-type and CAR null mice exposed to TCPOBOP (i.p.; 3 mg/kg bw/day) for 3 consecutive days and seven weeks revealed that TCPOBOP induced the expression of prototypical CAR-responsive genes (e.g. Cyp2b10) and lipogenic genes such as Fasn, Elovl6, Gpat and Pnpla3 (Marmugi et al., 2016).




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