Insights into Gender Bias: Rat Cytochrome P450 3A9

Abstract

Some members of the CYP3A subfamily show gender-dependent expression. Using quantitative real-time polymerase chain reaction, we report that female rats have 28-fold higher CYP3A9 mRNA levels than males in liver and 3.8-fold higher in lung. Furthermore, the CYP3A9 expression profile in kidney exhibits a regio-specific distribution, i.e., a 10-fold higher expression in cortex compared with medulla. Also, we observed tissue-specific estrogen regulation of the CYP3A9 message. Estrogen treatment caused a significant up-regulation in liver and a marked down-regulation both in the cortex and medulla of the kidney. Upon ovariectomy, hepatic and brain CYP3A9 expression were reduced significantly, but a modest increase in kidney expression was observed. The effects of ovariectomy on CYP3A9 gene expression were reversed upon exogenous estrogen treatment. CYP3A protein levels and hepatic microsomal activity toward benzphetamine after various treatments showed changes parallel to CYP3A9 mRNA levels. We report for the first time that CYP3A9 levels change dramatically during the course of pregnancy.

Effect of breed and gender on bovine liver cytochrome P450 3A (CYP3A) expression and inter-species comparison with other domestic ruminants

“…Since 1932, gender-related differences in the way by which animals metabolise drugs have been reported [15]; in this respect, a clear sexual dimorphism in the expression of hepatic genes, including some members of the CYP3A subfamily, has been documented in rodents and, particularly, in rats [1,13,20,24,28,33,42,45]. In cattle and other domestic animals, possible gendereffects on pharmacokinetics, including P450 drug metabolism, have already been described [4,6,8,9,17,18,36,40,52].…”

CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

“…Identification of genderspecific CYP isoforms in different species is, therefore, a first step in understanding gender-biased drug metabolism. 3 The genomic characterization of Cyp3a41 gene revealed an array of regulatory elements in the 5 0 flanking region including PXRE (ER6), HNF4, STAT5, CAAT and others. It has been recently reported that HNF4A knockout mice show lack of PXR gene expression, while hepatic conditional HNF4A deletion leads to reduced basal and inducible CYP3A expression.…”

“…In order to evaluate the role of E2 on CYP3A41 expression, female mice were ovariectomized and were treated with either estrogen (500 mg/kg) or sesame oil s.c. for a week. 3 At the end of the experiments, all mice including controls were killed, tissues excised, immediately frozen in liquid nitrogen, and stored at À801C until analyzed.…”

“…2 CYP3As are known to exhibit sex-, tissue-and age-dependent expression patterns. [3][4][5][6] To add to the complexity, CYP3As can be induced and suppressed by a wide variety of xenobiotics. 2 This makes CYP3A isoforms especially interesting because, apart from drug-drug interactions, interindividual variation in CYP3As may account for some of the differences in therapeutic outcome.…”

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

“…Ten micrograms of liver or intestinal ileum RNA was treated with DNase and reverse-transcribed with Superscript II (Invitrogen), and complementary DNAs were subjected to real-time PCR as described. 17 The PCR primer and probe sets were as follows: for Mrp4, forward primer 5Ј-tttacaagatggttcagcaactgg-3Ј, reverse primer 5Ј-ctgtccattggaggtgttcataac-3Ј, and probe 5Ј-cgaagccgctgccctcaccgaaac-3Ј; for Mdr1, forward primer 5Ј-gacttgatcgtggtgattgagaac-3Ј, reverse primer 5Ј-tggaccattgagaagtagatgcc-3Ј, and probe 5Ј-caaggagcacggcacccaccagc-3Ј; and for FGF15, forward primer 5Ј-gattgccatcaaggacgtcag-3Ј, reverse primer 5Ј-tcagcccgtatatcttgccg-3Ј, and probe 5Ј-tgcggtacctctgcatgagcgc-3Ј.…”