Minireview The Ontogeny, Distribution, and Regulation of Alcohol Dehydrogenase 3: Implications for Pulmonary Physiology

Class III alcohol dehydrogenase (ADH3), also termed formaldehyde dehydrogenase or S-nitrosoglutathione reductase, plays a critical role in the enzymatic oxidation of formaldehyde and reduction of nitrosothiols that regulate bronchial tone. Considering reported associations between formaldehyde vapor exposure and childhood asthma risk, and thus potential involvement of ADH3, we reviewed the ontogeny, distribution, and regulation of mammalian ADH3. Recent studies indicate that multiple biological and chemical stimuli influence expression and activity of ADH3, including the feedback regulation of nitrosothiol metabolism. The levels of ADH3 correlate with, and potentially influence, bronchial tone; however, data gaps remain with respect to the expression of ADH3 during postnatal and early childhood development. Consideration of ADH3 function relative to the respiratory effects of formaldehyde, as well as to other chemical and biological exposures that might act in an additive or synergistic manner with formaldehyde, might be critical to gain better insight into the association between formaldehyde exposure and childhood asthma. Formaldehyde has recently been suggested to represent a new class of indoor chemicals that pose as risk factors for respiratory and allergic effects that are distinct from other compounds (Mendell, 2007). The majority of this evidence arises from literature focusing on children (Krakowiak et al., 1998; Garrett et al., 1999; Franklin et al., 2000; Rumchev et al., 2002; Mendell, 2007). The disposition of drugs and environmental toxicants can be substantially different among adults and children and may alter susceptibility to adverse health effects (Ginsberg et al., 2002, 2007; Hattis et al., 2003; de Zwart et al., 2004; Barton, 2005; Makris et al., 2008). Indeed, formaldehyde is an example of a chemical that appears to be well metabolized in adults, but less is known about formaldehyde disposition in children. Recent efforts to understand differential susceptibility between adults and children have focused on physiological parameters (e.g., ventilation rate) and the ontogeny of enzymes that likely influence chemical disposition (Clewell et al., 2002; Hines and McCarver, 2002; McCarver and Hines, 2002; Benedetti et al., 2007; de Zwart et al., 2008; Dewoskin and Thompson, 2008; Hines, 2008). Although such efforts have rightly included the class I alcohol dehydrogenase (ADH1) responsible for ethanol clearance, comparatively little attention has been given to the class III isoform (ADH3) responsible for formaldehyde metabolism. This response may be due, in part, to the fact that ADH3 was long considered a ubiquitous housekeeping gene and has only recently been discovered to play an important role in multiple metabolic pathways with potentially far reaching consequences for cell physiology (Holmquist and Vallee, 1991; Hur and Edenberg, 1992; Deltour et al., 1999; Molotkov et al., 2002; Hoog et al., 2003; Liu et al., 2004). In particular, ADH3 reduction of the endogenous bronchodilator S-nitrosoglutathione (GSNO) has a profound influence on pulmonary physiology, which is underscored by reports that polymorphisms in this highly conserved gene can alter asthma risk in children (Edenberg et al., 1995; Liu et al., 2001; Henderson and Gaston, 2005; Que et al., 2005; Wu et al., 2007; Moore et al., 2009). We have previously described how ADH3 enzyme activity may influence pulmonary physiology and responses to formaldehyde (Thompson and Grafstrom, 2008; Thompson et al., 2008). In this study, we further review the distribution, ontogeny, and regulation of ADH3 in humans and laboratory animals to better characterize how ADH3 may interact with environmental exposures to influence pulmonary physiology and perhaps life stage susceptibility to asthma. Functions of Mammalian ADH3. ADH3 has been evolutionarily conserved from bacteria to vertebrates, and it is the evolutionary precursor to the ADH family (Danielsson and Jornvall, 1992; Hoog et al., 2001; Liu et al., 2001; Canestro et al., 2003). Gene duplication and mutation in the active site gave rise to gene members that lost the ability to metabolize formaldehyde, but gained activity toward short chain alcohols such as ethanol (Engeland et al., 1993). As shown in Fig. 1, ADH3 catalyzes the NAD -dependent oxidation of formalde1 Current address: ToxStrategies, Inc., Katy, Texas. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.109.027904. ABBREVIATIONS: ADH1, class I alcohol dehydrogenase; ADH3, class III alcohol dehydrogenase; GSNO, S-nitrosoglutathione; HMGSH, S-hydroxymethylglutathione; NO, nitric oxide; NOS, nitric oxide synthase; dpc, days postconception; uORF, upstream open reading frame; GSONH2, GSH sulfinamide; PDZ, postsynaptic density protein, Drosophila disc large tumor suppressing, and zonula occludens-1 protein. 0090-9556/09/3708-1565–1571 DRUG METABOLISM AND DISPOSITION Vol. 37, No. 8 U.S. Government work not protected by U.S. copyright 27904/3497435 DMD 37:1565–1571, 2009 Printed in U.S.A. 1565 at A PE T Jornals on Jne 1, 2017 dm d.aspurnals.org D ow nladed from