TY - JOUR
T1 - Altered Cholesterol Biosynthesis Affects Drug Metabolism
AU - Genaro-Mattos, Thiago C.
AU - Anderson, Allison
AU - Allen, Luke B.
AU - Korade, Zeljka
AU - Mirnics, Károly
N1 - Funding Information:
This work was supported by The National Institutes of Health NIMH MH110636 (K.M.), MN067234 (K.M.), and NICHD HD064727 (Z.K.). The authors also would like to thank the human fibroblast donors.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/3/2
Y1 - 2021/3/2
N2 - 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.
AB - 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.
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U2 - 10.1021/acsomega.0c05817
DO - 10.1021/acsomega.0c05817
M3 - Article
C2 - 33681590
AN - SCOPUS:85101993261
SN - 2470-1343
VL - 6
SP - 5490
EP - 5498
JO - ACS Omega
JF - ACS Omega
IS - 8
ER -