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Molecules 2012, 17(9), 10994-11009; doi:10.3390/molecules170910994

Inhibition of Cytochrome P450 3A in Rat Liver by the Diorganotin (IV) Compound di-n-Butyl-di-(4-chlorobenzo-hydroxamato)tin (IV) and Its Probable Mechanism

School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, Shanxi, China
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Received: 28 June 2012 / Revised: 28 August 2012 / Accepted: 3 September 2012 / Published: 12 September 2012
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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-chlorobenzohydroxamato)tin (IV) (DBDCT), a tin-based complex with high antitumor activity, and the probable mechanism(s) 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-chlorobenzohydroxamato)tin (IV) (DBDCT); inhibition; rat cytochrome P450 3A (CYP3A); di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT); inhibition; rat
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Zhang, Y.; Li, Y.; Li, Q. Inhibition of Cytochrome P450 3A in Rat Liver by the Diorganotin (IV) Compound di-n-Butyl-di-(4-chlorobenzo-hydroxamato)tin (IV) and Its Probable Mechanism. Molecules 2012, 17, 10994-11009.

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