Inhibition of Cytochrome P450 3A1/2 by Organotin Compound Di-N-Butyl-(4-chlorobenzohydroxamato)tin (IV) Chloride in Rat Liver and BRL Cells
Organotin compounds are high toxiferous chemicals and ubiquitous in our environment, which also have high biological activities. Di-n-butyl-(4-chlorobenzohydroxamato)tin (IV) chloride (DBDCT) represents a new paradigm for tin-based antitumor complexes with high activity. The inhibitory effect of DBDCT on cytochrome P450 3A(CYP3A) was studied in this article. The adult male SD rats were randomly divided into five groups with six in each and treated separately with saline, lipopolysaccharide (LPS, 5mg/kg), DBDCT (1.25, 2.5 and 5.0mg/kg, respectively) intraperitoneally for 2 days after induced with dexamethasone (DEX) at a dose of 100mg/kg for 4 days. The cytochrome P450 (CYP450) content was assayed by the method of Omura and Santa after the protein concentration detected by BCA assay kit. The activity of CYP3A was determined by the method of Nash. Western blot analysis was used to detect the expression of CYP3A1/2 at protein level in rat liver microsomes and Buffalo Rat Liver (BRL) cells. The results demonstrated that the activity of CYP450 and CYP3A were inhibited by exposure to DBDCT in rat liver compared with that of the blank control group. The expression of CYP3A1 and CYP3A2 proteins in rats treated with 1.25, 2.5 and 5.0mg/kg DBDCT were down-regulated respectively by 22.8% (p<0.01),24.3%(p<0.01), 58.4%(p<0.001) and 37.6%(p<0.001), 41.4%(p<0.001), 49.2%(p<0.001), than that of the blank control group. Immunoblot analysis of protein from BRL cell lysate demonstrated that the expression of CYP3A1 and CYP3A2 protein reduced separately by 11.4% (p<0.05), 34.2%(p<0.001), 45.5%(p<0.001), 64.9%(p<0.001), 78.8%(p<0.001) and 12.8% (p<0.05), 9.9% (p<0.05), 28.0% (p<0.001), 24.9% (p<0.001), 34.2% (p<0.001) after treated with DBDCT at a dose of 1µmol/L (for 24, 36, 48h) and 2µmol/L(for 24 and 48h). The activity of CYP3A in rat liver microsomes was decreased remarkably compared with that of the blank control group. Immunoblot analysis showed that the expression of CYP3A1/2 was inhibited significantly by DBDCT in rat liver and BRL cells.
Hexing Li, Qunjie Xu and Daquan Zhang
Y. X. Zhang et al., "Inhibition of Cytochrome P450 3A1/2 by Organotin Compound Di-N-Butyl-(4-chlorobenzohydroxamato)tin (IV) Chloride in Rat Liver and BRL Cells", Advanced Materials Research, Vols. 356-360, pp. 681-687, 2012