THE IMPACT OF OBESITY ON PROTEINS INVOLVED IN DRUG METABOLISM

Abstract

The study of obesity has increased in the recent years, as it is considered a major public health concern. In addition, obesity is often associated with several comorbidities such as diabetes mellitus and cardiovascular disease which require pharmacological intervention. Although several studies have investigated the impact of obesity on drug pharmacokinetics and the expression of drug metabolizing enzymes and transporters, few have examined its effect on the functional activity and the efficiency of drug metabolizing enzymes. In this thesis, we investigated the impact of obesity on phase I drug metabolizing enzymes (CYP450) functional activity using amiodarone as a test substrate and bisphenol A as a test substrate for phase II drug metabolizing enzymes (UGTs). These compounds were incubated with microsomes of liver and intestine of four groups of rats which were fed for 14 weeks either normal rodent food and water (control), normal rodent chow and high fructose-corn syrup water (HFCS), 45% high fat (HFD) diet and water, or 45% HFD and HFCS. Moreover, both compounds were also exposed to microsomes of lean and obese JCR rats, a model of genetic obesity. We found significant decrease in the hepatic intrinsic clearance of amiodarone in all groups fed on high caloric diet compared to control with no significant changes in intestinal intrinsic clearance of the drug between the groups. Regarding the functional activity of phase II drug metabolizing enzymes, we have found that the bisphenol A intrinsic clearance in the liver of all obese groups was increased compared to control. In addition, an increase in the intrinsic clearance of the compound was noticed in the intestinal microsomes of HFD and HFCS fed groups compared to control. With respect to the genetic obesity model, we found a decrease in the hepatic clearance of amiodarone but not with bisphenol A between lean and obese groups. Our findings indicate that high caloric diet-induced obesity can change the functional activity of drug metabolizing enzymes. This is consistent to literature data showing decreased expression of some of phase I metabolizing enzymes and increased expression of phase II metabolizing enzymes. Hence, obesity can potentially impact the pharmacokinetics of drugs as we reported the changes in efficiency of drug metabolizing enzymes and consequently, this will eventually impact the drug pharmacodynamics and individual response to drugs.