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Altered Cholesterol Biosynthesis Affects Drug Metabolism
Thiago C Genaro-Mattos1, Allison Anderson1, Luke B Allen1,2
1Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska 68105, United States.
ACS Omega
|March 8, 2021
Summary
Genetic variations in dehydrocholesterol reductase 7 (DHCR7) impact drug metabolism. Individuals with DHCR7 heterozygosity may experience altered therapeutic levels of medications like aripiprazole and cariprazine.
Area of Science:
- Biochemistry and Pharmacology
- Genetics and Drug Metabolism
Background:
- Cholesterol biosynthesis involves the enzyme dehydrocholesterol reductase 7 (DHCR7).
- DHCR7 plays a role in converting 7-dehydrocholesterol to cholesterol.
- Genetic variations in DHCR7 can affect metabolic pathways.
Purpose of the Study:
- To investigate the impact of DHCR7 single-allele mutations on drug metabolism.
- To examine the effects on aripiprazole (ARI) and cariprazine (CAR) metabolism.
- To assess potential clinical implications of DHCR7 heterozygosity.
Main Methods:
- Studied maternally exposed transgenic pups with Dhcr7 mutations.
- Measured levels of ARI, CAR, and their metabolites in liver and brain tissues.
- Analyzed cytochrome P450 2D6 (Cyp2d6) expression.
- Utilized wild-type (WT) and DHCR7 heterozygous human fibroblasts.
Main Results:
- ARI, CAR, and active metabolites were decreased in the liver and brain of Dhcr7 mutant animals.
- Increased turnover of ARI and CAR indicated enhanced metabolism in Dhcr7 mutant mice.
- Elevated Cyp2d6 levels in the liver of Dhcr7 mutant mice contributed to enhanced metabolism.
- DHCR7 heterozygous human fibroblasts showed lower drug levels.
Conclusions:
- DHCR7 heterozygosity is associated with altered metabolism of certain drugs.
- Individuals with DHCR7 heterozygosity may have reduced therapeutic drug levels.
- These individuals might be more susceptible to adverse drug reactions.
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