Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats

Abstract

The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5–20 mmole/kg. Ethanol was eliminated most rapidly, at 7.9 mmole/kg•h. Secondary alcohols (2-propanol-d7, 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol) were eliminated with first order kinetics at doses of 5–10 mmole/kg, and the corresponding ketones were formed and slowly eliminated with zero or first order kinetics. The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmole/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols. The Michaelis kinetic constants from in vitro studies (pH 7.3, 37 °C) with isolated rat liver enzyme were used to calculate the expected relative rates of metabolism in rats. The rates of elimination generally increased with increased activity of ADH, but a maximum rate of 6 ± 1 mmole/kg•h was observed for the best substrates, suggesting that ADH activity is not solely rate-limiting. Because secondary alcohols only require one NAD+ for the conversion to ketones whereas primary alcohols require two equivalents of NAD+ for oxidation to the carboxylic acids, it appears that the rate of oxidation of NADH to NAD+ is not a major limiting factor for metabolism of these alcohols, but the rate-limiting factors are yet to be identified.

Does Oxidative Stress Induced by Alcohol Consumption Affect Orthodontic Treatment Outcome?

“…In fact, CYP2E1 and ADH are strongly expressed not only in liver and the digestive tract, but also in other human oral cells as gingival fibroblasts, pulp, tongue and osteoblasts (Redetzki, 1960; Dong et al, 1996; Chen et al, 2006; Reichl et al, 2010; Plapp et al, 2015). Interestingly enough, it is well established that there is a good relation between CYP2E1 and EtOH in several digestive-related forms of cancer, e.g., mouth, pharynx, esophagus, colorectum and liver cancer (reviewed by Seitz and Wang, 2013).…”

“…CYP2E1 and ADH are both present in the liver (Redetzki, 1960; Plapp et al, 2015) and also expressed in human attached gingiva and tongue (Dong et al, 1996). Surprisingly enough, whereas ADH is expressed in stromal osteoblasts, CYP2E1 seems to be unexpressed (Chen et al, 2006).…”

Unusual Aldehyde Reductase Activity for Production of Full-length Fatty Alcohol by Cyanobacterial Aldehyde Deformylating Oxygenase  

“…The resulting fatty aldehyde is further converted to fatty alcohol by aldehyde reductase. However, high activities were observed for selected alcohols such as 1-propanol, 1butanol, 1-pentanol, isoamyl, 1-hexanol, 1-octanol, and benzyl alcohols with relatively high K m values [21].…”

Inversion of substrate stereoselectivity of horse liver alcohol dehydrogenase by substitutions of Ser-48 and Phe-93

“…Mammalian alcohol dehydrogenases oxidize a broad variety of alcohols and reduce the corresponding carbonyl compounds in the detoxification of primary and secondary alcohols [1,2]. Many ADHs specifically transfer the pro-R hydrogen of a primary alcohol to NAD + , which can be explained by a close contact of the pro-S hydrogen with the benzene ring of Phe-93 where even a methyl group would not easily be accommodated [3].…”