Inhibition of Cytochrome P450 3A in Rat Liver by the Diorganotin IV Compound di-n-Butyl-di-4-chlorobenzo-hydroxamatotin IV and Its Probable MechanismReportar como inadecuado




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School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, Shanxi, China





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Abstract The specific aims of this study were to evaluate the inhibition effect on CYP3A of di-n-butyl-di-4-chlorobenzohydroxamatotin IV DBDCT, a tin-based complex with high antitumor activity, and the probable mechanisms of this action. Adult male SD rats were treated separately with natural saline NS, lipopolysaccharide LPS, 5 mg-kg, DBDCT 1.25, 2.5 and 5.0 mg-kg intraperitoneally for 2 days after induction of CYP3A with dexamethasone DEX, 100 mg-kg for 4 days. Western blot analysis and fluorescent quantitation PCR FQ-PCR were conducted to determine the changes in expression of CYP3A, PXR, CAR and RXR. The biological accumulation of DBDCT and total Sn were determined by high-performance liquid chromatography HPLC and atomic fluorescence spectrometry AFS. CYP450 content and CYP3A activities were significantly inhibited p 0.05 in DBDCT-treated rats compared with the control group, as was the expression of CYP3A p 0.05 at both protein and mRNA levels. In DBDCT-treated groups, the expression of PXR protein and mRNA increased, while the expression of CAR decreased. The biological accumulation of DBDCT and Sn in rat livers treated with DBDCT was high. The accumulation of DBDCT and Sn due to the inhibition of CYP3A may be involved in the mechanism of toxicity of DBDCT in rat liver.

Keywords: cytochrome P450 3A CYP3A; di-n-butyl-di-4-chlorobenzohydroxamatotin IV DBDCT; inhibition; rat cytochrome P450 3A CYP3A; di-n-butyl-di-4-chlorobenzohydroxamatotin IV DBDCT; inhibition; rat





Autor: Yunxia Zhang, Yunlan Li * and Qingshan Li *

Fuente: http://mdpi.com/



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