Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved?

Abstract

Background: In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts a modulating role on CYP3A, in our hypothesis. Objective: To evaluate the effect of metabolic syndrome on CYP3A drug-metabolizing activity/expression in guinea pigs. Methods: Hepatic microsomes were prepared from male Hartley guinea pigs fed with a control, a high-fat high sucrose (HFHS) or a high-fat high fructose diet (HFHF). Domperidone was selected as a probe substrate of CYP3A and formation of four of its metabolites was evaluated using high-performance liquid chromatography. CYP3A protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction, respectively. Hepatic fatty infiltration was evaluated using standard Oil Red O staining. Triglyceride and free fatty acid liver content were also quantified. Results: Microsomal CYP3A activity was significantly decreased in both HFHS and HFHF diet groups versus the control diet group. Significant decreases of CYP3A mRNA and protein expression were observed in both HFHS and HFHF diet groups. Oil Red O staining showed a massive liver fatty infiltration in the HFHS and HFHF diet groups, which was not observed in the control diet group. Both triglyceride and free fatty acid liver content were significantly increased in the HFHS and HFHF diet groups. Conclusion: Diet-induced metabolic syndrome decreases CYP3A expression/activity in guinea pigs. This may ultimately lead to variability in drug response, ranging from lack of effect to life-threatening toxicity.Introduction CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs (Danielson, 2002). There is a considerable variability in the expression and activity of CYP3A4 among the general population (10-to 100-fold), which cannot be solely explained by genetic factors (Elens et al., 2011). There is evidence that diseases or pathologic states may modulate human and animal CYP3A (Yoshinari et al., 2006;Dostalek et al., 2011). The variability in CYP3A4-associated drug metabolism is known as a major determinant of drug response and/or toxicity (Lamba et al., 2002). Currently, more than 30% of the United States population has a body mass index . 30 kg/m 2 , which puts those people in the obese category (Ogden et al., 2006). Ninety percent of obese patients present histologically proven fatty liver infiltration-related abnormalities (Moretto et al., 2003). Some pharmacokinetic studies performed in obese populations reported a significant decrease in the clearance of drugs, particularly when it is CYP3A-mediated (Abernethy et al., 1984;Caraco et al., 1995). Diabetes is a widespread chronic disease, which was affecting over 350 million people worldwide in 2011 (Whiting et al., 2011). Common como...

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