The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake.
Ethanol 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 x 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+) (Aldh2(2)), while drinker rats present two Aldh2 alleles (Aldh2(1) and Aldh2(3)) with four- to fivefold higher affinities for NAD+. Further, the ALDH2 encoded by Aldh2(1) also shows a 33% higher Vmax than those encoded by Aldh2(2) and Aldh2(3). Maximal voluntary ethanol intakes are the following: UChA Aldh2(2)/Aldh2(2) = 0.3-0.6 g/kg/day; UChB Aldh2(3)/Aldh2(3) = 4.5-5.0 g/kg/day; UChB Aldh2(1)/Aldh2(1) = 7.0-7.5 g/kg/day. In F2 offspring of UChA x UChB, the Aldh2(2)/Aldh2(2) genotype predicts a 40-60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh2(2)/Aldh2(2) 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.
Quintanilla
María E
ME
Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Chile. equintanilla@med.uchile.cl
Israel
Yedy
Y
Sapag
Amalia
A
Tampier
Lutske
L
D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002755:Choice Behavior; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005838:Genotype; D024101:Mitochondrial Proteins / Q000235:genetics*; D009243:NAD / Q000235:genetics*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013695:Temperance
D002492:Central Nervous System Depressants; D024101:Mitochondrial Proteins; D009243:NAD; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat