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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: dmd.109.026963v1 37/7/1505    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Löfgren, S. Articles by Ingelman-Sundberg, M. PubMed PubMed Citation Articles by Löfgren, S. Articles by Ingelman-Sundberg, M.

Regulation of Human CYP2C18 and CYP2C19 in Transgenic Mice: Influence of Castration, Testosterone, and Growth Hormone

Safety Assessment, AstraZeneca Research and Development, Södertälje, Sweden (S.L., R.F.-S.); Department of Physiology and Pharmacology, Section of Pharmacokinetics, Karolinska Institutet, Stockholm, Sweden (R.M.B., M.C., J.M., M.I.-S.); Drug Metabolism and Pharmacokinetics and Bioanalysis, Bioscience, Medivir AB, Huddinge, Sweden (Y.T.); and Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts (D.J.W.)

The hormonal regulation of human CYP2C18 and CYP2C19, which are expressed in a male-specific manner in liver and kidney in a mouse transgenic model, was examined. The influence of prepubertal castration in male mice and testosterone treatment of female mice was investigated, as was the effect of continuous administration of growth hormone (GH) to transgenic males. Prepubertal castration of transgenic male mice suppressed the expression of CYP2C18 and CYP2C19 in liver and kidney to female levels, whereas expression was increased for the endogenous female-specific mouse hepatic genes Cyp2c37, Cyp2c38, Cyp2c39, and Cyp2c40. Testosterone treatment of female mice increased CYP2C18 and CYP2C19 expression in kidney, and to a lesser extent in liver, but was without effect in brain or small intestine, where gene expression was not gender-dependent. Continuous GH treatment of transgenic males for 7 days suppressed hepatic expression of CYP2C19 (>90% decrease) and CYP2C18 (50% decrease) but had minimal effect on the expression of these genes in kidney, brain, or small intestine. Under these conditions, continuous GH induced all four female-specific mouse liver Cyp2c genes in males to normal female levels. These studies indicate that the human CYP2C18 and CYP2C19 genes contain regulatory elements that respond to the endogenous mouse hormonal profiles, with androgen being the primary regulator of male-specific expression in kidney, whereas the androgen-dependent pituitary GH secretory pattern is the primary regulator of male-specific expression in liver in a manner that is similar to the regulation of the endogenous gender-specific hepatic genes.