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Xenobiotica
the fate of foreign compounds in biological systems
Volume 36, 2006 - Issue 12
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Original

Marmoset CYP3A21, a model for human CYP3A4: Protein expression and functional characterization of the promoter

, , , , , , & show all
Pages 1210-1226 | Received 25 Jul 2006, Accepted 15 Aug 2006, Published online: 11 Aug 2009
 

Abstract

Due to its small size and the relative evolutionary proximity, the marmoset has been proposed as a model for studies of human drug interactions and metabolism. The current study investigated the expression and regulation of marmoset CYP3A using mass spectrometry and reporter gene techniques. Expression levels of hepatic marmoset CYP3A protein range from 51 to 123 pmol mg−1 total protein (mean 85.2 pmol mg−1, n = 10) and CYP3A21 is the dominant hepatic CYP3A protein in marmosets. The sequence similarity between human CYP3A4 and CYP3A21 across the first 7.5 kb of the cloned CYP3A21 promoter is 88% within the xenobiotic-responsive enhancer module (XREM) and the proximal promoter. Both regulatory modules confer transcriptional activation of CYP3A21-luciferase reporter gene constructs cotransfected with hPXR in intestinal LS174T cells. The pronounced response to rifampin and the moderate response to dexamethasone were similar to those observed with CYP3A4. Taken collectively, these data establish substantial similarities in expression and gene regulation between marmoset CYP3A21 and human CYP3A4. CYP3A21 may be an equivalent of CYP3A4 in New World monkeys, consistent with the phylogenetic relationship between these genes. The marmoset, therefore, appears to be a suitable in vivo model to study CYP3A4 function and regulation.

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