Dsp quattro no such volume8/11/2023 In addition, some nuclear factors, such as HNF-4α (CYP3A4), HNF-4 and USF-1 (CYP3A23) are likely needed for optimal CYP3A expression. It has been shown that the regulation of CYP3A expression involves different nuclear receptors, such as GR, PXR, CAR and VDR. Regulation of CYP3A gene expression in humans is one of the best known among the CYP genes. There are many known drugs which are substrates for CYP3A, including: psychotropics, calcium channel blockers (e.g., nifedipine), cyclosporine, macrolide antibiotics (e.g., erythromycin), antifungal drugs (e.g., clotrimazole, ketoconazole), and endogenous substances, mainly steroids (testosterone, progesterone, estradiol, and androstenedione), as well as bile acids and retinol. The CYP3A subfamily is the most abundant in human liver and belongs to the most expressed subfamilies in animals. CYP isoforms are involved in the metabolism of high-activity endogenous substrates (e.g., steroids, arachidonic acid, neurotransmitters, and vitamins), most of clinically important drugs and harmful xenobiotics. Further studies into the hypothalamic–pituitary–gonadal hormones in DSP-4 treated mice may explain sex-specific differences in CYP3A regulation, whereas investigation of monoaminergic receptor sensitivity in the hypothalamic/pituitary areas of NET –/– mice will allow for understanding a lack of changes in the CYP3A activity in the NET-KO animals.Ĭytochrome P450 (CYP) enzymes are members of the superfamily of heme-containing monooxygenases. The results with DSP-4 treated mice showed sex-dependent differences in the regulation of liver CYP3A by the brain noradrenergic system (with only males being responsive), and revealed that the NET knockout did not affect CYP3A in both sexes. The NET knockout did not affect the CYP3A activity/protein in both sexes. The level of CYP3A protein was not changed. At the same time, DSP-4 reduced the CYP3A activity in males, but not in females. ResultsĭSP-4 evoked a selective decrease in the noradrenaline level in the brain of male and female mice. The CYP3A protein level was estimated by Western blotting. The activity of CYP3A was measured as the rate of 6β-hydroxylation of testosterone in liver microsomes. DSP-4 was injected intraperitoneally as a single dose (50 mg/kg ip.) to WT mice. ![]() The experiments were conducted on C57BL/6J WT and NET –/– male/female mice. In the present work, a comparative study on the effect of intraperitoneal administration of the noradrenergic neurotoxin DSP-4 and the knockout of noradrenaline transporter (NET-KO) on the CYP3A in the liver of male and female mice was performed. Our earlier studies have shown that the brain noradrenergic system regulates cytochrome P450 (CYP) in rat liver via neuroendocrine mechanism.
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