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J. Biol. Chem., Vol. 278, Issue 38, 36085-36090, September 19, 2003

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Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid^*

Andrei Molotkov and Gregg Duester 

From the OncoDevelopmental Biology Program, Burnham Institute, La Jolla, California 92037

Vitamin A (retinol) is a nutrient that is essential for developmental regulation but toxic in large amounts. Previous genetic studies have revealed that alcohol dehydrogenase Adh1 is required for efficient clearance of excess retinol to prevent toxicity, thus demonstrating that the mechanism involves oxidation of excess retinol to retinoic acid (RA). Whereas Adh1 plays a dominant role in the first step of the clearance pathway (oxidation of retinol to retinaldehyde), it is unknown what controls the second step (oxidation of retinaldehyde to RA). We now present genetic evidence that aldehyde dehydrogenase Aldh1a1, also known as retinaldehyde dehydrogenase Raldh1, plays a dominant role in the second step of retinol clearance in adult mice. Serum RA levels following a 50 mg/kg dose of retinol were reduced 72% in Raldh1^-/- mice and 82% in Adh1^-/- mice. This represented reductions in RA synthesis of 77–78% for each mutant after corrections for altered RA degradation in each. After retinol dosing, serum retinaldehyde was increased 2.5-fold in Raldh1^-/- mice (indicating defective retinaldehyde clearance) and decreased 3-fold in Adh1^-/- mice (indicating defective retinaldehyde synthesis). Serum retinol clearance following retinol administration was decreased 7% in Raldh1^-/- mice and 69% in Adh1^-/- mice. LD₅₀ studies indicated a small increase in retinol toxicity in Raldh1^-/- mice and a large increase in Adh1^-/- mice. These observations demonstrate that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulating retinol rather than retinaldehyde.

Received for publication, April 9, 2003 , and in revised form, June 16, 2003.

^* This work was supported by National Institutes of Health Grant EY13969 (to G. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: OncoDevelopmental Biology Program, Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3138; Fax: 858-646-3195; E-mail: duester{at}burnham.org.

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