Families of retinoid dehydrogenases regulating vitamin A function

Abstract

Vitamin A (retinol) and provitamin A (b-carotene) are metabolized to specific retinoid derivatives which function in either vision or growth and development. The metabolite 11-cis-retinal functions in light absorption for vision in chordate and nonchordate animals, whereas all-trans-retinoic acid and 9-cis-retinoic acid function as ligands for nuclear retinoic acid receptors that regulate gene expression only in chordate animals. Investigation of retinoid metabolic pathways has resulted in the identification of numerous retinoid dehydrogenases that potentially contribute to metabolism of various retinoid isomers to produce active forms. These enzymes fall into three major families. Dehydrogenases catalyzing the reversible oxidation/reduction of retinol and retinal are members of either the alcohol dehydrogenase (ADH) or short-chain dehydrogenase/reductase (SDR) enzyme families, whereas dehydrogenases catalyzing the oxidation of retinal to retinoic acid are members of the aldehyde dehydrogenase (ALDH) family. Compilation of the known retinoid dehydrogenases indicates the existence of 17 nonorthologous forms: five ADHs, eight SDRs, and four ALDHs, eight of which are conserved in both mouse and human. Genetic studies indicate in vivo roles for two ADHs (ADH1 and ADH4), one SDR (RDH5), and two ALDHs (ALDH1 and RALDH2) all of which are conserved between humans and rodents. For several SDRs (RoDH1, RoDH4, CRAD1, and CRAD2) androgens rather than retinoids are the predominant substrates suggesting a function in androgen metabolism as well as retinoid metabolism.

Retinoid metabolism: a balancing act

“…Oxidation of retinol to retinaldehyde requires the activities of several alcohol dehydrogenases (see figure) 5 . The second step-oxidation of retinaldehyde to alltrans retinoic acid-requires the action of three related retinaldehyde dehydrogenases and is generally believed to be the rate-limiting step in the biosynthesis of all-trans retinoic acid.…”

Interaction between alcohol dehydrogenase II gene, alcohol consumption, and risk for breast cancer

“…In combination with xanthine oxidoreductase, ADH may lead to the formation of reactive oxygen species that themselves have been linked to types of DNA damage typically observed in breast cancer and therefore contribute to breast carcinogenesis (Wright et al, 1999). Furthermore, Class I ADH plays an important role in the provitamin A (beta-carotene) metabolism, oxidizing all-trans-retinol and 9-cis-retinol, and might play a role in hydroxysteroid metabolism (Duester, 2000). Therefore, there seems to be evidence that some forms of ADH may play important roles in human tissues other than the liver, including the breast.…”

Retinoids and spermatogenesis: Lessons from mutant mice lacking the plasma retinol binding protein

“…RA synthesis is catalyzed by retinaldehyde dehydrogenases encoded by the Aldh1a1, Aldh1a2, Aldh1a3, and Aldh8a1 genes (Duester, 2000;Lin et al, 2003). In vitamin A-deficient Rbp4-null seminiferous tubules at end stages of degeneration (VADD14), Aldh1a1 transcripts were detected in Sertoli cells at levels similar to those in Leydig cells (Fig.…”

“…Vitamin A proper (retinol; ROL) is biologically inactive. Within cells, ROL is either esterified with long-chain fatty acids for storage as retinyl esters (RE), or oxidized to its aldehyde form (retinaldehyde, RAL) and subsequently to its acid form (retinoic acid, RA; reviewed in Napoli, 1999;Duester, 2000). With the exception of vision, which requires RAL (reviewed in Palczewski and Saari, 1997), the vitamin A-dependent biological processes require RA that acts as a local hormonal signal through binding to two types of nuclear receptors the retinoic acid receptors (RAR␣, ␤, and ␥), and the rexinoid receptors (RXR␣, ␤, and ␥; reviewed in Chambon, 1996).…”