REVIEW: The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake

Addiction Biology - Tập 11 Số 3-4 - Trang 310-323 - 2006
Marı́a Elena Quintanilla1, Yedy Israel2,1, Amalia Sapag2, Lutske Tampier1
1Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine and
2Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, University of Chile, Chile

Tóm tắt

ABSTRACTEthanol non‐drinker (UChA) and drinker (UChB) rat lines derived from an original Wistar colony have been selectively bred at the University of Chile for over 70 generations. Two main differences between these lines are clear. (1) Drinker rats display a markedly faster acute tolerance than non‐drinker rats. In F2 UChA × UChB rats (in which all genes are ‘shuffled’), a high acute tolerance of the offspring predicts higher drinking than a low acute tolerance. It is further shown that high‐drinker animals ‘learn’ to drink, starting from consumption levels that are one half of the maximum consumptions reached after 1 month of unrestricted access to 10% ethanol and water. It is likely that acquired tolerance is at the basis of the increases in ethanol consumption over time. (2) Non‐drinker rats carry a previously unreported allele of aldehyde dehydrogenase‐2 (Aldh2) that encodes an enzyme with a low affinity for Nicotinamide‐adenine‐dinuclectide (NAD+) (Aldh22), while drinker rats present two Aldh2 alleles (Aldh21 and Aldh23) with four‐ to fivefold higher affinities for NAD+. Further, the ALDH2 encoded by Aldh21 also shows a 33% higher Vmax than those encoded by Aldh22 and Aldh23. Maximal voluntary ethanol intakes are the following: UChA Aldh22/Aldh22 = 0.3–0.6 g/kg/day; UChB Aldh23/Aldh23 = 4.5–5.0 g/kg/day; UChB Aldh21/Aldh21 = 7.0–7.5 g/kg/day. In F2 offspring of UChA × UChB, the Aldh22/Aldh22 genotype predicts a 40–60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh22/Aldh22 animals depends on the existence of a maternally derived low‐activity mitochondrial reduced form of nicotinamide‐adenine‐dinucleotide (NADH)‐ubiquinone complex I. The latter does not influence ethanol consumption of animals exhibiting an ALDH2 with a higher affinity for NAD+. An illuminating finding is the existence of an ‘acetaldehyde burst’ in animals with a low capacity to oxidize acetaldehyde, being fivefold higher in UChA than in UChB animals. We propose that such a burst results from a great generation of acetaldehyde by alcohol dehydrogenase in pre‐steady‐state conditions that is not met by the high rate of acetaldehyde oxidation in mitochondria. The acetaldehyde burst is seen despite the lack of differences between UChA and UChB rats in acetaldehyde levels or rates of alcohol metabolism in steady state. Inferences are drawn as to how these studies might explain the protection against alcoholism seen in humans that carry the high‐activity alcohol dehydrogenase but metabolize ethanol at about normal rates.

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Tài liệu tham khảo

10.1093/oxfordjournals.alcalc.a008166

10.1016/0028-3908(77)90137-X

10.1074/jbc.M304998200

Aragon CM, 1992, The effect of 3‐amino‐1,2,4‐triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action, Neuropharmacology, 31, 712

10.1016/0006-2952(92)90042-H

10.1016/0024-3205(85)90579-X

10.1016/0091-3057(91)90397-K

10.1124/jpet.102.042960

10.1016/0006-291X(92)91621-V

10.1111/j.1530-0277.2002.tb02626.x

10.1086/302540

Crabbe JC, 1979, Rapid development of tolerance to the hypothermic effect of ethanol in mice, J Pharmacol Exp Ther, 208, 128

Cronholm T, 1985, Hydrogen transfer between ethanol molecules during oxidoreduction in vivo, Biochem J, 15, 315, 10.1042/bj2290315

10.1111/j.1530-0277.1988.tb00265.x

10.1021/tx00008a005

10.1016/S0014-2999(98)00414-2

10.1007/s002130050763

10.1111/j.1530-0277.2001.tb02369.x

Eriksson CJP, 1993, Human blood acetaldehyde Update 1992, Alcohol Alcohol Suppl, 2, 9

10.1042/bj1520709

10.1016/0006-2952(77)90310-0

10.1016/S0091-3057(80)80045-1

10.1084/jem.194.5.571

10.1111/j.1530-0277.1992.tb01892.x

10.1007/s002130000622

10.1111/j.1530-0277.1997.tb04255.x

10.1016/S0140-6736(82)92722-2

Higuchi S, 1994, Polymorphisms of ethanol metabolizing enzyme genes and alcoholism, Alcohol Alcohol Suppl, 2, 29

10.1016/0003-9861(75)90483-X

Israel Y, 1970, Effect of 2,4‐dinitrophenol on the rate of ethanol elimination in the rat in vivo, Biochem J, 120, 447, 10.1042/bj1200447

10.1016/S0741-8329(96)00083-3

10.1016/0741-8329(94)90036-1

10.1016/0005-2744(75)90174-6

10.1016/S0896-6273(00)80557-7

10.1016/0091-3057(95)02055-1

10.1111/j.1600-0773.1976.tb03184.x

10.1016/0741-8329(96)00008-0

Mardones J, 1983, Thirty‐two years of selection of rats by ethanol preference: UChA and UChB strains, Neurobehav Toxicol Teratol, 5, 171

Mardones J, 1984, Effects of different diets on voluntary consumption of ethanol in UChA and UChB rats, Acta Physiol Pharmacol Latinoam, 34, 31

Mardones J, 1953, Heredity of experimental alcohol preference in rats. II. Coefficient of heredity, Q J Stud Alcohol, 14, 1, 10.15288/qjsa.1953.14.001

10.1042/bj1270633

Mellamby E, 1919, Alcohol: its absorption into and disappearance from the blood under different conditions, MRC Spec Rep Ser (Lond), 31, 1

10.1007/BF01978064

10.1097/01.ALC.0000108667.79219.4D

Parrilla R, 1974, Functional compartmentation of acetaldehyde oxidation in rat liver, J Biol Chem, 249, 4926, 10.1016/S0021-9258(19)42410-1

10.1007/978-1-4684-7529-6_4

10.1016/j.tips.2004.01.001

10.1016/S0741-8329(01)00128-8

10.1016/S0741-8329(01)00197-5

10.1016/0741-8329(93)90024-I

10.1016/0741-8329(95)00037-2

10.1016/S0741-8329(00)00092-6

10.1016/j.alcohol.2003.07.001

10.1097/01213011-200506000-00009

10.1096/fj.04-2172com

10.1007/BF02245438

Rawat AK, 1977, Effects of fructose and other substances on ethanol and acetaldehyde metabolism in man, Res Commun Chem Pathol Pharmacol, 16, 281

10.1097/00008571-200308000-00009

10.1176/ajp.151.2.184

Segovia‐Riquelme N, 1970, Alcohol and Alcoholism, 56

Segovia‐Riquelme N, 1956, Alcohol metabolism in ‘drinking’ and ‘non‐drinking’ rats, J Biol Chem, 233, 399, 10.1016/S0021-9258(18)65149-X

10.1016/0006-2952(74)90565-6

10.1016/0741-8329(85)90076-X

Strachan T, 1999, Human Molecular Genetics

10.1016/0376-8716(79)90043-7

Tampier L, 1979, Catalase mediated oxidation of ethanol by rat brain homogenates, IRCS Med Sci-Biochem, 7, 389

10.1016/0741-8329(86)90042-X

10.15288/jsa.1999.60.168

10.1080/13556219971524

10.1080/13556210220139488

10.15288/jsa.2002.63.257

10.1080/13556210310001602185

Tampier L, 1984, Biological similarities and differences between rats genetically different in alcohol preference, Alcohol Alcohol, 19, 203

10.1016/0741-8329(88)90035-3

Tampier L, 1981, Effects of 3‐amino‐1,2,4‐triazole pretreatment on ethanol induced narcosis in UChA and UChB rats with different previous ethanol intake, IRCS Med Sci-Biochem, 9, 188

Tampier L, 1985, Effects of diets decreasing ethanol consumption on acetaldehyde metabolism in UChA and UChB rats, Alcohol Alcohol, 20, 411

Tampier L, 1994, Acetaldehyde metabolism: differences between UChA and UChB rats, Alcohol Alcohol, 29, 751

10.1016/0741-8329(95)00014-I

10.1080/13556219971696

10.15288/jsa.2000.61.647

10.1080/1355621961000124996

10.1046/j.1471-4159.2001.00492.x

10.1038/24614

Thomasson HR, 1991, Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men, Am J Hum Genet, 48, 677

10.1042/bj1350577a

10.1007/BF02197242

10.1097/01.fpc.0000182777.95555.56

10.1016/0091-3057(83)90345-3

10.1016/0006-2952(80)90521-3

10.1111/j.1530-0277.1998.tb03958.x

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Addiction Biology

Tập 11 Số 3-4

310-323

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