Role of alcohol dehydrogenases in steroid and retinoid metabolism.

Abstract

Retinoid and steroid hormones play an important role in the regulation of differentiation and maintenance of a wide range of animal tissues. These tissues include reproductive organs, liver, kidney, heart, brain, and skin of species from fish to humans. Several isozymes of cytosolic NAD+-dependent 40 kDa subunit molecular weight alcohol dehydrogenases catalyze oxidation and reduction of retinoid and steroid substrates in vitro. The isozymes are grouped into classes based on the similarities in amino acid sequence and their substrate specificities. Currently, a total of six classes of mammalian ADHs are known (Jornvall and Hoog, 1995). Each class has a characteristic tissue-specific and developmental pattern of expression (Edenberg and Bosron, 1996). Class I ADHs are basic isozymes with a wide range of Km for ethanol (0.05–36 mM). In humans, class I is comprised of multiple molecular forms, β1β1, β2β2, β3β3, γ1γ1, γ2γ2, α α, and their heterodimers. During development, ᾲᾳ is the first ADH isozyme detectable in fetal liver. β-ADH appears by mid-gestation, and γ-ADH is first detected about six month after birth. Human class II π-ADH has a relatively high KM for ethanol (34 mM) and is found in fetal and adult liver. The ubiquitously expressed class III ADH, also known as glutathione-dependent formaldehyde dehydrogenase, is not saturable with ethanol and is not active with either steroid or retinoid alcohols. Human class IV σ-ADH exhibits high KM for ethanol (28 mM) and is present in the adult stomach, esophagus and epithelium. In mice embryos, class IV ADH is detected on day 7.5 of development in the craniofacial region as well as trunk and forelimb bud mesenchyme (Ang, H.L. et al., 1996). Little is known about the catalytic properties of human class V and deermouse class VI ADH isozymes.