Abstract
Phenobarbital (PB) promotes liver tumorigenesis in rodents, in part through activation of the constitutive androstane receptor (CAR) and the consequent changes in hepatic gene expression and increases in hepatocyte proliferation. A typical effect of CAR activation by PB is a marked induction of Cyp2b10 expression in the liver; the latter has been suspected to be vital for PB-induced hepatocellular proliferation. This hypothesis was tested here by using a Cyp2a(4/5)bgs-null (null) mouse model in which all Cyp2b genes are deleted. Adult male and female wild-type (WT) and null mice were treated intraperitoneally with PB at 50 mg/kg once daily for 5 successive days and tested on day 6. The liver-to-body weight ratio, an indicator of liver hypertrophy, was increased by 47% in male WT mice, but by only 22% in male Cyp2a(4/5)bgs-null mice, by the PB treatment. The fractions of bromodeoxyuridine-positive hepatocyte nuclei, assessed as a measure of the rate of hepatocyte proliferation, were also significantly lower in PB-treated male null mice compared with PB-treated male WT mice. However, whereas few proliferating hepatocytes were detected in saline-treated mice, many proliferating hepatocytes were still detected in PB-treated male null mice. In contrast, female WT mice were much less sensitive than male WT mice to PB-induced hepatocyte proliferation, and PB-treated female WT and PB-treated female null mice did not show significant difference in rates of hepatocyte proliferation. These results indicate that CYP2B induction plays a significant, but partial, role in PB-induced hepatocyte proliferation in male mice.
Footnotes
- Received April 19, 2017.
- Accepted May 23, 2017.
This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA092596], National Institute of Environmental Health Sciences [Grant ES020867], National Institute of General Medical Sciences [Grant GM082978], and in part by the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences].
Parts of this work were previously presented as a poster at the following workshop: Li L, Bao X, Zhang QY, Negishi M, Ding X (2015) Role of CYP2B in phenobarbital-induced hepatocyte proliferation in mice. 54th Annual Meeting of the Society of Toxicology; 22–26 Mar 2015; San Diego, CA.
- U.S. Government work not protected by U.S. copyright
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