Androgen-Dependent Expression of CUX2 mRNA in the Pig Liver Is Associated with That of Drug Metabolizing Enzymes and Drug Transporters

Abstract

We previously identified androgen-dependent sex differences in the mRNA expression of drug metabolizing enzymes (DMEs), including CYPs, sulfotransferases and uridine 5′-diphospho-glucuronosyltransferases, and drug transporters in the pig liver and kidney. To elucidate the mechanism for such sex differences in pigs, we herein focused on the key regulators cut-like homeobox 2 (Cux2), B-cell lymphoma 6 (Bcl6), and signal transducer and activator of transcription 5b (Stat5b), which are reported to be responsible for the sex-biased gene expression of Cyps in the mouse liver. We used real-time RT-PCR to examine androgen-dependent sex differences in the mRNA levels of these regulators in the liver and kidney basically using Meishan and Landrace pigs. Significant sex differences (male > female) in the level of CUX2 mRNA were detected in the liver of both breeds, and levels were significantly decreased in males by castration and increased in castrated males and intact females by administering testosterone propionate. No such clear androgen-dependent sex differences in hepatic BCL6 or STAT5B mRNA expression were observed in either breed. In the kidney, androgen-dependent gene expression of these regulators was not observed. In the liver, CUX2 mRNA expression closely correlated with that of DMEs and drug transporters, which were previously shown to have androgen-dependent expression. Together, these findings demonstrate that hepatic CUX2 mRNA is expressed in an androgen-dependent manner, and strongly suggest that CUX2 plays a key role in the androgen-dependent gene expression of hepatic DMEs and drug transporters.