Alcohol Metabolism and Cardiovascular Response in an Alcoholic Patient Homozygous for the ALDH2*2 Variant Gene Allele

Authors

  • Yi-Chyan Chen,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Ru-Band Lu,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Giia-Sheun Peng,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Ming-Fang Wang,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Hsu-Kun Wang,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Huei-Chen Ko,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Yue-Cune Chang,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Jang-Jih Lu,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Ting-Kai Li,

    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • Shih-Jiun Yin

    Corresponding author
    1. Graduate Institute of Medical Sciences (Y.-C. Chen, S.-J.Y.) and Department of Biochemistry (M.-F.W., H.-K.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China; Departments of Psychiatry (R.-B.L.), Neurology (G.-S.P.) and Pathology (J.-J.L.), Tri-Service General Hospital National Defense Medical Center, Taipei; Institute of Behavioral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (H.-C.K.); Department of Mathematics, Tamkang University, Tamsui, Taiwan (Y.-C.Chang); Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (T.-K.L.).
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  • This work was supported by National Science Council Grants 88-2316-B016-005Y and 89-2314-B016-028 (S.-J.Y.); and 88-2314-B016-081 and 89-2314-B016-024 (R.-B.L.); National Health Research Institutes Grant GT-EX89B939P (R.-B.L. and S.-J.Y.); Department of Health Grants 86-TD-125, 87-TD-1127, and 88-TD-1107 (H.-C.K); and National Institute on Alcohol Abuse and Alcoholism Grants AA07611 and AA02342 (T.-K.L.).

Reprint requests: Shih-Jiun Yin, Department of Biochemistry, National Defense Medical Center, P.O. Box 90048, Taipei, Taiwan, ROC; Far: 886-2-2368-2327; E-mail: yinsj@tpts5.seed.net.tw

Abstract

Background: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism.

Methods: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography.

Results: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 μM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2—ALDH2*2/*2 individuals than the ADH2*1/*1—ALDH2*1/*1 individuals.

Conclusions: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2—ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

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