Background and Purpose The sensitivity to the intoxicating effects of alcohol as well as its adverse medical consequences differ markedly among individuals, which reflects in part differences in alcohol's absorption, distribution, metabolism, and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol's brain bioavailability, however, is not well understood. Experimental Approach The ADME of C-11 labeled alcohol, CH311CH2OH, 1 and C-11 and deuterium dual labeled alcohol, CH311CD2OH, 2 in baboons was compared based on the principle that C–D bond is stronger than C–H bond, thus the reaction is slower if C–D bond breaking occurs in a rate-determining metabolic step. The following ADME parameters in peripheral organs and brain were derived from time activity curve (TAC) of positron emission tomography (PET) scans: peak uptake (Cmax); peak uptake time (Tmax), half-life of peak uptake (T1/2), the area under the curve (AUC60min), and the residue uptake (C60min). Key Results For 1 the highest uptake occurred in the kidney whereas for 2 it occurred in the liver. A deuterium isotope effect was observed in the kidneys in both animals studied and in the liver of one animal but not the other. The highest uptake for 1 and 2 in the brain was in striatum and cerebellum but 2 had higher uptake than 1 in all brain regions most evidently in thalamus and cingulate. Alcohol's brain uptake was significantly higher when given intravenously than when given orally and also when the animal was pretreated with a pharmacological dose of alcohol. Conclusion and Implications The study shows that alcohol metabolism in peripheral organs had a large effect on alcohol's brain bioavailability. This study sets the stage for clinical investigation on how genetics, gender and alcohol abuse affect alcohol's ADME and its relationship to intoxication and medical consequences.
References
[1]
Correa M, Salamone JD, Segovia KN, Pardo M, Longoni R, et al. (2012) Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci Biobehav Rev 36: 404–430.
[2]
Guo R, Ren J (2010) Alcohol and acetaldehyde in public health: from marvel to menace. Int J Environ Res Public Health 7: 1285–1301.
[3]
Peng GS, Chen YC, Tsao TP, Wang MF, Yin SJ (2007) Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele. Pharmacogenet Genomics 17: 845–855.
[4]
Li D, Zhao H, Gelernter J (2011) Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet.
[5]
Yokoyama A, Omori T (2003) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Jpn J Clin Oncol 33: 111–121.
[6]
Yokoyama A, Omori T, Yokoyama T (2010) Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. Keio J Med 59: 115–130.
[7]
Salaspuro MP (2003) Alcohol consumption and cancer of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 17: 679–694.
[8]
Hommer D, Momenan R, Kaiser E, Rawlings R (2001) Evidence for a gender-related effect of alcoholism on brain volumes. Am J Psychiatry 158: 198–204.
[9]
Jacobson R (1986) The contributions of sex and drinking history to the CT brain scan changes in alcoholics. Psychol Med 16: 547–559.
[10]
Chen CH, Walker J, Momenan R, Rawlings R, Heilig M, et al.. (2011) Relationship Between Liver Function and Brain Shrinkage in Patients with Alcohol Dependence. Alcohol Clin Exp Res.
[11]
Sato N, Lindros KO, Baraona E, Ikejima K, Mezey E, et al. (2001) Sex difference in alcohol-related organ injury. Alcohol Clin Exp Res 25: 40S–45S.
[12]
Friel PN, Baer JS, Logan BK (1995) Variability of ethanol absorption and breath concentrations during a large-scale alcohol administration study. Alcohol Clin Exp Res 19: 1055–1060.
[13]
Volkow ND, Hitzemann R, Wolf AP, Logan J, Fowler JS, et al. (1990) Acute effects of ethanol on regional brain glucose metabolism and transport. Psychiatry Res 35: 39–48.
[14]
Karahanian E, Quintanilla ME, Tampier L, Rivera-Meza M, Bustamante D, et al. (2011) Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects. Alcohol Clin Exp Res 35: 606–612.
[15]
Wilkinson PK, Sedman AJ, Sakmar E, Lin YJ, Wagner JG (1977) Fasting and nonfasting blood ethanol concentrations following repeated oral administration of ethanol to one adult male subject. J Pharmacokinet Biopharm 5: 41–52.
[16]
Cronholm T, Jones AW, Skagerberg S (1988) Mechanism and regulation of ethanol elimination in humans: intermolecular hydrogen transfer and oxidoreduction in vivo. Alcohol Clin Exp Res 12: 683–686.
[17]
Cronholm T (1985) Incorporation of the 1-pro-R and 1-pro-S hydrogen atoms of ethanol in the reduction of acids in the liver of intact rats and in isolated hepatocytes. Biochem J 229: 323–331.
[18]
Kuikka J, Keinanen M, Solin O, Heselius SJ, Nanto V (1980) Liver sinusoidal permeability to ethanol and xenon molecules. J Biomed Eng 2: 87–88.
[19]
Bernstein J, Martinez B, Escobales N, Santacana G (1983) The pulmonary ethanol metabolizing system (PET). Res Commun Chem Pathol Pharmacol 39: 49–67.
[20]
Michoudet C, Baverel G (1987) Metabolism of acetaldehyde in human and baboon renal cortex. Ethanol synthesis by isolated baboon kidney-cortex tubules. FEBS Lett 216: 113–117.
[21]
Upadhya SC, Ravindranath V (2002) Detection and localization of protein-acetaldehyde adducts in rat brain after chronic ethanol treatment. Alcohol Clin Exp Res 26: 856–863.
[22]
Zimatkin SM, Liopo AV, Satanovskaya VI, Bardina Lr, et al. (2001) Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. II: Studies in selectively bred rats and mice. Alcohol Clin Exp Res 25: 982–988.
[23]
Zimatkin SM, Liopo AV, Slychenkov VS, Deitrich RA (2001) Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. I: Studies in outbred animals. Alcohol Clin Exp Res 25: 976–981.
[24]
DeGrazia JA, Rodden AF, Teresi JD, Busick DD, Walz DR (1975) Radioscintigraphic studies of 11C distribution in cats given 1-11C-ethanol. J Nucl Med 16: 73–76.
[25]
Hetherington HP, Telang F, Pan JW, Sammi M, Schuhlein D, et al. (1999) Spectroscopic imaging of the uptake kinetics of human brain ethanol. Magn Reson Med 42: 1019–1026.
[26]
Amberg R, Furmaier R, Hirt H, Urban R (2002) Regional ethanol absorption of the human brain during the influx phase measured by means of the Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET). Blutalkohol 39: 11.
[27]
Howard RJ, Slesinger PA, Davies DL, Das J, Trudell JR, et al. (2011) Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution. Alcohol Clin Exp Res 35: 1561–1573.
[28]
Fowler JS, Wolf AP, MacGregor RR, Dewey SL, Logan J, et al. (1988) Mechanistic positron emission tomography studies: demonstration of a deuterium isotope effect in the monoamine oxidase-catalyzed binding of [11C]L-deprenyl in living baboon brain. J Neurochem 51: 1524–1534.
[29]
Lundquist F, Hansen LL (1989) Deuterium isotope effects as a tool in the study of ethanol oxidation in rat liver microsomes. Pharmacol Toxicol 65: 45–54.
[30]
Lundquist F, Iversen HL, Hansen LL (1990) Deuterium D(V/K) isotope effects on ethanol oxidation in hepatocytes: importance of the reverse ADH-reaction. Pharmacol Toxicol 66: 244–251.
[31]
Xiang Y, Shen J (2011) In vivo detection of intermediate metabolic products of [1-(13) C]ethanol in the brain using (13) C MRS. NMR Biomed 24: 1054–1062.
[32]
Raichle ME, Eichling JO, Straatmann MG, Welch MJ, Larson KB, et al. (1976) Blood-brain barrier permeability of 11C-labeled alcohols and 15O-labeled water. Am J Physiol 230: 543–552.
[33]
Ramchandani VA, Bosron WF, Li TK (2001) Research advances in ethanol metabolism. Pathol Biol (Paris) 49: 676–682.
[34]
Li TK, Yin SJ, Crabb DW, O'Connor S, Ramchandani VA (2001) Genetic and environmental influences on alcohol metabolism in humans. Alcohol Clin Exp Res 25: 136–144.
[35]
Damgaard SE (1981) Primary deuterium and tritium isotope effects upon V/K in the liver alcohol dehydrogenase reaction with ethanol. Biochemistry 20: 5662–5669.
[36]
Damgaard SE (1980) Isotope effect in peroxidation of deuterium-labelled ethanol by liver catalase. Biochem J 191: 613–618.
[37]
Corrall RJ, Rodman HM, Margolis J, Landau BR (1974) Stereospecificity of the oxidation of ethanol by catalase. J Biol Chem 249: 3181–3182.
[38]
Lieber CS (1988) The microsomal ethanol oxidizing system: its role in ethanol and xenobiotic metabolism. Biochem Soc Trans 16: 232–239.
[39]
Bell LC, Guengerich FP (1997) Oxidation kinetics of ethanol by human cytochrome P450 2E1. Rate-limiting product release accounts for effects of isotopic hydrogen substitution and cytochrome b5 on steady-state kinetics. J Biol Chem 272: 29643–29651.
[40]
Bell-Parikh LC, Guengerich FP (1999) Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde. J Biol Chem 274: 23833–23840.
[41]
Ramchandani VA (2004) Genetic aspects of alcohol metabolism, in Nutrition and Alcohol: Linking Nutrient Interactions and Dietary Intake; Watson RR, Preedy VP, editors: CRC Press, Boca Raton. 12 p.
[42]
Michoudet C, Baverel G (1987) Characteristics of acetaldehyde metabolism in isolated dog, rat and guinea-pig kidney tubules. Biochem Pharmacol 36: 3987–3991.
[43]
Bernstein J, Basilio C, Martinez B (1990) Ethanol sulfation by the pulmonary ethanol metabolizing system (PET). Res Commun Chem Pathol Pharmacol 68: 219–234.
Deelchand DK, Shestov AA, Koski DM, Ugurbil K, Henry PG (2009) Acetate transport and utilization in the rat brain. J Neurochem 109 Suppl 146–54.
[47]
Christie IC, Price J, Edwards L, Muldoon M, Meltzer CC, et al. (2008) Alcohol consumption and cerebral blood flow among older adults. Alcohol 42: 269–275.
[48]
Friel PN, Logan BK, O'Malley D, Baer JS (1999) Development of dosing guidelines for reaching selected target breath alcohol concentrations. J Stud Alcohol 60: 555–565.
[49]
Chen JC, Lin CC, Ng CC, Chiu TF, Shyr MH (2007) Uneven distribution of ethanol in rat brain following acute administration, with the highest level in the striatum. J Stud Alcohol Drugs 68: 649–653.
[50]
Gulyas B, Halldin C, Sandell J, Karlsson P, Sovago J, et al. (2002) PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand 106: 325–332.
[51]
Volkow ND, Wang GJ, Begleiter H, Porjesz B, Fowler JS, et al. (2006) High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch Gen Psychiatry 63: 999–1008.
[52]
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, et al. (2007) Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 27: 12700–12706.
[53]
Wang GJ, Volkow ND, Franceschi D, Fowler JS, Thanos PK, et al. (2000) Regional brain metabolism during alcohol intoxication. Alcohol Clin Exp Res 24: 822–829.
[54]
Zhu W, Volkow ND, Ma Y, Fowler JS, Wang GJ (2004) Relationship between ethanol-induced changes in brain regional metabolism and its motor, behavioural and cognitive effects. Alcohol Alcohol 39: 53–58.
[55]
Adalsteinsson E, Sullivan EV, Mayer D, Pfefferbaum A (2006) In vivo quantification of ethanol kinetics in rat brain. Neuropsychopharmacology 31: 2683–2691.
[56]
Julkunen RJ, Tannenbaum L, Baraona E, Lieber CS (1985) First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption. Alcohol 2: 437–441.
