The impact of cholesterol and its metabolites on drug metabolism

Global prevalence of Western-type diet has increased in the last decades resulting in occurrence of certain chronic diseases. This type of diet is also linked to high-cholesterol intake and increase in blood cholesterol. Many of the molecular mechanisms of dealing with increased levels of cholesterol and its metabolites have been elucidated in animal models and humans. It is also evident that cholesterol metabolism is closely connected to drug metabolism. Cholesterol/bile acids and drugs share many transporters, enzymes and regulatory proteins which are key points in the crosstalk.

This review presents an overview of the effect of cholesterol and its metabolites on drug metabolism with special emphasis on species-specific differences. The article focuses on the role of nuclear receptors farnesoid X receptor, vitamin D receptor and liver X receptor in the regulation of drug metabolism genes and the role of cholesterol biosynthesis intermediates, oxysterols and bile acids in the induction of drug metabolism through pregnane X receptor.

Studies show that the regulation of drug metabolism by sterols is multileveled. Many species-dependent differences were observed which hinder the transfer of findings from model animals to humans. As of now, there is little evidence available for cholesterol impact on drug metabolism in vivo in humans. There is also the need to confirm the results obtained in animal models and in vitro analyses in human cells but this is very difficult given the current lack of tools.