Distinct functions forAldh1 andRaldh2 in the control of ligand production for embryonic retinoid signaling pathways

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123

103

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. LD 50 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.

Section: Adh4mentioning

confidence: 98%

Section: Growth Of Raldh1mentioning

confidence: 99%

Section: Raldh1 Acts Downstream Of Adh1 In Retinoid Metabolismmentioning

confidence: 99%

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

Molotkov

Duester

2003

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123

103

“…Studies on the second step of RA synthesis, oxidation of retinal to RA, have yielded consistent results indicating that three forms of cytosolic aldehyde dehydrogenase referred to as retinaldehyde dehydrogenase (RALDH) participate in RA synthesis (1). In vitro activities are reported for RALDH1 (4), RALDH2 (5-7), and RALDH3 (8), plus in vivo activities are reported for RALDH1 and RALDH2 (9,10). Gene disruption studies demonstrate that RALDH2 is essential for catalyzing the second step of RA synthesis during development as Raldh2 Ϫ/Ϫ embryos die at mid-gestation and almost totally lack RA (11,12).…”

mentioning

confidence: 94%

Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice

Molotkov

Deltour²,

Foglio³

et al. 2002

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The ability of class I alcohol dehydrogenase (ADH1) and class IV alcohol dehydrogenase (ADH4) to metabolize retinol to retinoic acid is supported by genetic studies in mice carrying Adh1 or Adh4 gene disruptions. To differentiate the physiological roles of ADH1 and ADH4 in retinoid metabolism we report here the generation of an Adh1/4 double null mutant mouse and its comparison to single null mutants. We demonstrate that loss of both ADH1 and ADH4 does not have additive effects, either for production of retinoic acid needed for development or for retinol turnover to minimize toxicity. During gestational vitamin A deficiency Adh4 and Adh1/4 mutants exhibit completely penetrant postnatal lethality by day 15 and day 24, respectively, while 60% of Adh1 mutants survive to adulthood similar to wild-type. Following administration of a 50-mg/kg dose of retinol to examine retinol turnover, Adh1 and Adh1/4 mutants exhibit similar 10-fold decreases in retinoic acid production, whereas Adh4 mutants have only a slight decrease. LD 50 studies indicate a large increase in acute retinol toxicity for Adh1 mutants, a small increase for Adh4 mutants, and an intermediate increase for Adh1/4 mutants. Chronic retinol supplementation during gestation resulted in 65% postnatal lethality in Adh1 mutants, whereas only ϳ5% for Adh1/4 and Adh4 mutants. These studies indicate that ADH1 provides considerable protection against vitamin A toxicity, whereas ADH4 promotes survival during vitamin A deficiency, thus demonstrating largely non-overlapping functions for these enzymes in retinoid metabolism.

“…There are reports of retinaldehydespecific dehydrogenases that catalyze this step (32)(33)(34)(35)(36)(37)(38). Of particular interest, at least one of these retinaldehyde dehydrogenases is specifically expressed in tracheal epithelial cells in rat, with a putative role in the conversion of retinaldehyde to retinoic acid in these cells.…”

mentioning

confidence: 99%

Characterization of a Novel Airway Epithelial Cell-specific Short Chain Alcohol Dehydrogenase/Reductase Gene Whose Expression Is Up-regulated by Retinoids and Is Involved in the Metabolism of Retinol

Soref¹,

Di²,

Hayden

et al. 2001