Altered Cholesterol Biosynthesis Affects Drug Metabolism

Abstract

The last step of cholesterol biosynthesis is the conversion of 7-dehydrocholesterol (7-DHC) into cholesterol, a reaction catalyzed by dehydrocholesterol reductase 7 (DHCR7). Investigation of the effect of Dhcr7 single-allele mutations on the metabolism of aripiprazole (ARI) and cariprazine (CAR) in maternally exposed transgenic pups revealed that ARI, CAR, and their active metabolites were decreased in the liver and brain of Dhcr7+/–. This difference in the drug and metabolite levels resulted in an increased turnover of ARI and CAR in tissues from Dhcr7+/– animals, indicating an enhanced metabolism, which was at least partially due to increased levels of Cyp2d6 in the liver of Dhcr7+/– mice. Finally, experiments with both WT and DHCR7+/– human fibroblasts revealed lower drug levels in DHCR7+/– heterozygous cells. Our findings have potential clinical implications, as DHCR7 heterozygosity is present in 1–3% in the human population, and these individuals might have reduced therapeutic levels of Cyp2d6-metabolized medications and are putatively more susceptible to unwanted side effects.