Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism.

ABSTRACT: The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 ^-/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 ^-/- background (TgCES1). Ces1 ^-/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 ^-/-

SUBMITTER: Gan C 

PROVIDER: S-EPMC9978993 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature