Title: Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice.
Authors: Li, Lei; Bao, Xiaochen; Zhang, Qing-Yu; Negishi, Masahiko; Ding, Xinxin
Published In Drug Metab Dispos, (2017 08)
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.
PubMed ID: 28546505
MeSH Terms: Animals; Aryl Hydrocarbon Hydroxylases/deficiency; Aryl Hydrocarbon Hydroxylases/genetics; Aryl Hydrocarbon Hydroxylases/physiology*; Cell Proliferation/drug effects; Cell Proliferation/physiology; Cytochrome P450 Family 2/physiology*; Enzyme Induction/drug effects; Enzyme Induction/physiology; Female; Hepatocytes/drug effects*; Hepatocytes/enzymology*; Hypnotics and Sedatives/pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenobarbital/pharmacology*; Steroid Hydroxylases/deficiency; Steroid Hydroxylases/genetics; Steroid Hydroxylases/physiology*