![]() This study reports the characterization of the genomic structure of Cyp3a41 and identification of putative steroid and orphan nuclear receptor binding sites in its 5′ flanking region. This led us to investigate the molecular basis of CYP3A41 expression. Such a sexual dimorphism is interesting, and understanding the regulation of these genes will be the first step taken to elucidate gender-dependent clinical responses. 10 Sakuma et al 10 cloned CYP3A41 and showed that the highest levels of CYP3A41 expression were reached after sexual maturation. Recently, it has been shown that CYP3A41 is expressed in a female-specific pattern. Such a reciprocal activation of each other's response elements could in turn imply a fail-safe protection against toxicants. 22 These observations along with several reports clearly indicate crosstalk between the two receptors. 20, 21 PXR and CAR fall under the same nuclear subfamily NR1, and share RXR as their heterodimeric partner. 14 Alternatively, recent evidence suggests the role of another important xenobiotic receptor, CAR, in activating CYP3A expression through PXR defined elements. 19 Additionally, PXR null mice exhibit a total lack of CYP3A11 induction following pregnenolone-16α-carbonitrile (PCN) or dexamethasone (Dex) treatment. 17, 18 This is inferred from the fact that PXREs are commonly present in various promoter regions of mouse CYP3As and are activated by known CYP3A inducers. 15, 16 PXR, a novel orphan nuclear receptor, has been implicated in CYP3A subfamily induction in response to various xenobiotics. 4, 7, 8, 9, 10, 11, 12 CYP3A11 is the most studied isoform and is regulated by nuclear receptors pregnane X receptor (PXR) 13, 14 and constitutive androstane receptor (CAR). To date, six mouse CYP3A isoforms namely CYP3A11, CYP3A13, CYP3A16, CYP3A25, CYP3A41 and CYP3A44 have been identified. 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. 3, 4, 5, 6 To add to the complexity, CYP3As can be induced and suppressed by a wide variety of xenobiotics. 2 CYP3As are known to exhibit sex-, tissue- and age-dependent expression patterns. ![]() 1 The phase I metabolism of more than 50% of therapeutic drugs is catalyzed mainly by the CYP3A subfamily. Cytochrome P450s (CYPs) are a family of heme thiolate proteins responsible for the oxidative metabolism of various steroids, bile acids, hormones, eicosanoids and a large number of clinically active drugs. ![]()
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