Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner

Biochemical Pharmacology
Samuel ArnoldNina Isoherranen

Abstract

all-trans retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Specifically the concentrations of atRA are spatiotemporally controlled in target tissues such as the liver and the testes. While the enzymes of the aldehyde dehydrogenase 1A family (ALDH1A) are believed to control the synthesis of atRA, a direct relationship between altered ALDH1A activity and tissue atRA concentrations has never been shown. To test whether inhibition of ALDH1A enzymes decreases atRA concentrations in a tissue specific manner, the potent ALDH1A inhibitor WIN 18,446 was used to inhibit ALDH1A activity in mice. The ALDH1A expression, atRA formation kinetics, ALDH1A inhibition by WIN 18,446 and WIN 18,446 disposition were used to predict the time course and extent of inhibition of atRA formation in the testis and liver. The effect of WIN 18,446 on atRA concentrations in testis, liver and serum were measured following single and multiple doses of WIN 18,446. ALDH1A1 and ALDH1A2 were responsible for the majority of atRA formation in the testis while ALDH1A1 and aldehyde oxidase contributed to atRA formation in the liver. Due to the different complement of enzymes contributing to atRA formation in different tissue...Continue Reading

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Citations

Apr 17, 2018·The Journal of Reproduction and Development·Mizuki SakaiSeiji Takashima
Feb 16, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Suya WangAlexander R Moise
Mar 10, 2017·The Journal of Pharmacology and Experimental Therapeutics·Jing JingNina Isoherranen
Apr 28, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Faith StevisonNina Isoherranen
Feb 21, 2018·Biology of Reproduction·Michael D Griswold
Jan 6, 2021·Molecular Reproduction and Development·Rachel L GewissMichael D Griswold
Aug 17, 2019·Pharmacology & Therapeutics·Nina Isoherranen, Guo Zhong
Nov 3, 2020·Journal of Nutritional Science and Vitaminology·Yuka NagataMakoto Kadowaki
Dec 24, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Guo ZhongNina Isoherranen
May 3, 2021·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Michael HaenischJisun Paik
Aug 11, 2021·The Journal of Pharmacology and Experimental Therapeutics·Matt LabenskiAlan F Corin

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