Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin

Abstract

Alcohols and aldehydes in the metabolic pathways of ethanol and serotonin are substrates for alcohol dehydrogenases (ADH) of class I and II. In addition to the reversible alcohol oxidation/aldehyde reduction, these enzymes catalyse aldehyde oxidation. Class-I gg ADH catalyses the dismutation of both acetaldehyde and 5-hydroxyindole-3-acetaldehyde (5-HIAL) into their corresponding alcohols and carboxylic acids. The turnover of acetaldehyde dismutation is high (k cat = 180 min 21 ) but saturation is reached first at high concentrations (K m = 30 mm) while dismutation of 5-HIAL is saturated at lower concentrations and is thereby more efficient (K m = 150 mm; k cat = 40 min 21 ). In a system where NAD + is regenerated, the oxidation of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid proceeds with concentration levels of the intermediary 5-HIAL expected for a two-step oxidation. Butanal and 5-HIAL oxidation is also observed for class-I ADH in the presence of NADH. The class-II enzyme is less efficient in aldehyde oxidation, and the ethanol-oxidation activity of this enzyme is competitively inhibited by acetate (K i = 12 mm) and 5-hydroxyindole-3-acetic acid (K i = 2 mm).Reduction of 5-HIAL is efficiently catalysed by class-I gg ADH (k cat = 400 min 21 ; K m = 33 mm) in the presence of NADH. This indicates that the increased 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratio observed after ethanol intake may be due to the increased NADH/NAD + ratio on the class-I ADH.Keywords: alcohol dehydrogenase; alcohol metabolism; aldehydes; sequential oxidation; serotonin metabolism.The alcohol dehydrogenase (ADH) family is the major enzyme system for metabolism of ingested ethanol [1,2]. In addition to ethanol, a range of substrates has been identified for these enzymes and a possible mechanism for ethanol-induced metabolic changes may be interference with other activities of ADH (Fig. 1). For example, ethanol affects human noradrenaline, dopamine and serotonin metabolism by increasing the relative formation of the alcohol products, 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylethanol and 5-hydroxytryptophol (5-HTOL), while decreasing the formation of the carboxylic acid products, 4-hydroxy-3-methoxymandelic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole-3-acetic acid (5-HIAA) [3,4]. Clinical monitoring of recent drinking takes advantage of the elevated 5-HTOL/5-HIAA ratio which can be detected in urine for several hours after ethanol is no longer measurable [5,6]. The ADH activities for noradrenaline and dopamine metabolites have been characterized, and alcohols and aldehydes in these catabolic pathways serve as good substrates for ADH of both class I and class II [7,8]. It has also been shown that the serotonin metabolite 5-HTOL is an ADH substrate [9].In addition to reversible alcohol oxidation/aldehyde reduction, horse class-I and human class-I and class-II ADH catalyse aldehyde oxidation and thereby mimic the activity of aldehyde dehydrogenase (ALDH) [10±12]. Incubation of ADH with aldehyde and N...

Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia

“…ADH1B metabolizes substrates in pathways involving serotonin, norepinephrine, dopamine, and alcohol (Consalvi et al 1986;Helander et al 1994;Svensson et al 1999; and thus is relevant to psychiatric disorders. Although we did not find a predisposing mutation in any exons of AGA for schizophrenia, there are known mutations of AGA that cause the lysosomal storage disease, Aspartylglucosaminuria (OMIM# 208400).…”

Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase

“…In DOPEGAL metabolism, hepatic class I ADH isozymes catalyze the conversion of MHPG to the aldehyde, MOPEGAL (Mardh et al, 1985), which is then converted by hepatic ALDH to VMA (Messiha, 1978). Liver class I ADH enzymes have also been reported to efficiently catalyze the reduction of DOPAL (K m ϭ 8.9 M), and it has been reported that class I ADH is involved in the metabolism of catecholamines (Mardh and Vallee, 1986;Svensson et al, 1999). The presence of ADH class 1 mRNA has been reported in adult rat brain (Martinez et al, 2001).…”

Hepatoprotective activity of Sapindus mukorossi and Rheum emodi extracts: In vitro and in vivo studies

“…Studies in human Hep G2 cells have shown that ethanol is cytotoxic to Hep G2 cells, which are transduced to express P-450 2E1 (CYP 2E1) and this toxicity is apoptotic in nature [4] predominantly in the liver. The main pathways for hepatic oxidation of ethanol to acetaldehyde involve alcohol dehydrogenase [5] and are associated with the reduction of NAD + to NADH [6] . The magnitude of derangement of liver by disease or hepatotoxins is generally measured by the level of glutamate pyr uvate transaminase (ALT), glutamate oxaloacetate transaminase (AST), alkaline phosphatase (ALP), bilirubin, albumin, and whole liver homogenate.…”