Aldehyde dehydrogenase-2, deficiency

Crabb DW, Edenberg HJ, Bosron WF, Li T-K. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2 2 allele is dominant. J Clin Invest 1989 83 314—316. 

Some functional clarification of these problems has been provided by recent comparative genotyping of alcoholics and non-alcoholics. Studies in Chinese (83-85) and in Japanese (86,87), supported by meta-analysis (88), indicated significantly reduced frequencies of beta2 and gammai in alcoholics, besides the usually present aldehyde dehydrogenase deficiency (see below). It means that the high rate of ethanol conversion to the toxic and unpleasant acetaldehyde tends to reduce ethanol consumption, particularly if acetaldehyde is slowly metabolized. 

Some populations, most notably East Asians, exhibit an unusual response after drinking ethanol. The symptoms include facial flushing, vasodilation, and tachycardia. These individuals apparently have a genetic deficiency of the enzyme aldehyde dehydrogenase, which leads to an accumulation of acetaldehyde even after they drink relatively small amounts of ethanol. If drugs such as metronidazole, griseofulvin, quinacrine, the hypoglycemic sulfonylureas, phenothiazines, and phenylbutazone are coadministered with ethanol, a similar accumulation of acetaldehyde may occur. 

Human polymorphisms in several enzymes involved in toluene metabolism are known. In Mongoloid populations, deficiency in the low form of aldehyde dehydrogenase H2 (ALDH2) is common approximately half of the Japanese population lacks this enzyme. In ALDH2-deficient exposed workers, an increased level of benzyl alcohol was found, but benzaldehyde was not detectable urinary excretion of hippurate was decreased in the deficient individuals. The CYPlAl polymorphism, alcohol consumption and smoking were all associated with decreased hippurate excretion, but the interdependence was too complex to allow detailed conclusions on the mechanisms to be drawn (Kawamoto et al., 1995). 

Some people, primarily of Asian descent, have a genetic deficiency in the activity of the mitochondrial form of aldehyde dehydrogenase. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a flushing reaction similar to that seen with the combination of disulfiram and ethanol. 

Unlike many DNA alkylators, cyclophosphamide shows modest selectivity for cancer cells. Healthy tissues in a patient have high levels of aldehyde dehydrogenase (ALDH). ALDH reduces the potency of cyclophosphamide by oxidizing 6.32 to 6.34, an inactive compound. Cancerous cells tend to be deficient in ALDH and more prone to damage by cyclophosphamide. 

Goedde and Agarwal (96) list test results from 29 different populations and a total of 3248 subjects. The data can be summarized by the statements that Central Asian, East Asian, and South-East Asian populations showed deficiencies in the order of 30%. The deficiency was absent in European, Near-East, and African populations. North American Indians showed deficiency rates of 2-5%, South American Indians of 40-45%. O Dowd et al. (101) have shown that the functional enzyme deficiency in South American Indians must be due to a different mutation than the deficiency in Asians. This observation raises interesting questions regarding the biological significance of the mitochondrial aldehyde dehydrogenase. 

Kamino K, Nagasaka K, Imagawa M, Yamamoto H, Yoneda H, Held A, Kitamura S, Ntimekata K, Miki T, Ohta S (2000) Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer s disease in the Japanese population. Biochem Biophys Res Commun 273 192-196... 

Intolerance. Inter-ethnic variation in tolerance to alcohol is well recognised, for Asian persons, particularly Japanese, develop flushing, headache and nausea after what are, by Caucasian standards, small amounts of the substance. Genetic deficiency of aldehyde dehydrogenase with slow metabolism of (toxic) acetaldehyde may explain these features. 

An interesting sidelight, Asians are often deficient in aldehyde dehydrogenase. About 50% of Japanese and Chinese people lack the mitochondrial enzyme. About 40 10 of native South Americans also lack the enzyme. This results in a number of adverse reactions to drinking alcohol, including facial flushing from dilation of peripheral blood vessels and increased heart rate. Apparently, these reactions are provoked by an unusual buildup of plasma acetaldehyde. 

Of the deficits unrelated to the glycolipids which show an abundant clinical literature but less interest manifested by scientists in the field of lipidomics are ceroid lipofuscinosis (the deficiency in palmitoyl-protein thioesterase (PPT)) and the Sjogren-Larsson syndrome, a defect of ALDH3A2 gene which encodes fatty aldehyde dehydrogenase (FALDH). It is pertinent to question the reason for such differences between clinical and basic scientific interests reflected in literature citations. 

Fatty alcohohNAD oxidoreductase is a complex enzyme which consists of two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and to fatty acid that is to say a fatty alcohol dehydrogenase and a fatty aldehyde dehydrogenase (FALDH) activity. Sjogren-Larsson cells were selectively deficient in the FALDH component and had normal activity of fatty alcohol dehydrogenase. Intact fibroblast oxidized octadecanol to fatty acid at <10% of the normal rate but oxidized octadecanal normally confirming that FALDH is specifically affected (Rizzo and Craft, 1991). 

Rizzo W.B., Craft D.A., Sjogren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol NAD+ oxidoreductase in cultured fibroblasts, The Journal of clinical investigation 88 (1991) 1643-1648. 

Willemsen M.A., Cruysberg J.R., Rotteveel J.J., Aandekerk A.L., Van Domburg P.H., Deutman A.F., Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjogren-Larsson syndrome, American journal of ophthalmology 130 (2000) 782-789. 

Ethanol is absorbed at aU levels of the gastrointestinal tract. Acetaldehyde is the initial product of metabolism of ethanol. There are no differences between men and women in plasma levels of ethanol following its intravenous administration. Women have higher blood levels than men after oral ingestion, possibly because they have lower activity of gastric alcohol dehydrogenase. A characteristic feature of ethanol biodisposition is that its elimination via metabolism follows zero-order kinetics. Certain persons of Asian descent are deficient in aldehyde dehydrogenase and may experience a disulfiram-like reaction at low doses of ethanol. The answer is (A). 

Acquired Immune Deficiency Syndrome Aldehyde Dehydrogenase Gene Cytosolic Aldehyde Dehydrogenase Alkaliphilic Bacteria Ampicillin Resistance Arginosuccinate Synthetase Autonomously Replicating Sequence Adenosine Triphosphate Gold... 

The corresponding open-chain aldehyde, formed by hydrolysis, can be oxidized back to glutamate by pyrroline 5-carboxylate dehydrogenase. 145a 147 Lack of this enzyme is associated with the human genetic deficiency causing hyperprolinemia.147-1483... 

The enzymes are widely distributed in microorganisms, plants, and animals. " Three Mo-MPT enzymes have been found in mammals (1) xanthine dehydrogenase see Dehydrogenase) has many, varied roles in purine catabolism, drug metabolism, and oxidative stress response, (2) aldehyde oxidase is important in drug metabolism and the synthesis of retinoic acid from retinal, and (3) sulfite oxidase plays a cmcial role in the detoxification of sulfite produced in the degradation of cysteine and methionine. Genetic Mo-MPT deficiency in... 

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