Abstract
Caffeine (1,3,7-trimethylxanthine, CA) is a compound usually contained in beverages such as coffee and tea. CA is known to pharmacologically antagonize ethanol. Thus, the simultaneous intake of CA and ethanol takes place very commonly. Sometimes, toxic interactions also occur following combined intake of these two compounds. In this study, we conducted in vitro experiments to examine the interaction between ethanol and CA at high concentrations by observing mixed-function oxidation reaction using human liver microsomes. After incubation of the mixtures, CA and its three main metabolites theobromine (3,7-dimethylxanthine, TB), paraxanthine (1,7-dimethylxanthine, PX), and theophylline (1,3-dimethylxanthine, TP) were measured by high-performance liquid chromatography with ultraviolet detection. As results, the production of PX, the main metabolite of CA, was consistently inhibited by 24%–53% (P < 0.05) by high ethanol concentrations (20, 40, and 60 mM), but that of TP or TB was not. These results suggest that pharmacological or toxicological effects of CA may be enhanced by simultaneous use of ethanol and CA in humans.
References
Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133
Kalow W, Tang BK (1991) Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Phamacol Ther 50:508–519
Butler MA, Iwasaki M, Guengerich FP, Kadlubar F (1989) Human cytochrome P450A (P-4501A2), the phenacetin, Odeethylase, is primarily responsible for the hepatic 3- demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci USA 86:7696–7700
Nowell S, Sweeney C, Hammons G, Kadlubar FF, Lang NP (2002) CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 11:377–383
Aklillu E, Carrillo JA, Makonnen E, Bertilsson L, Ingelman-Sundberg M (2003) Xanthine oxidase activity is influenced by environmental factors in Ethiopians. Eur J Clin Pharmacol 59:533–536
Asprodini EK, Zifa E, Papageorgiou I, Benakis A (1998) Determination of N-acetylation phenotyping in a Greek population using caffeine as a metabolic probe. Eur J Drug Metab Phamacokinet 23:501–516
Kalow W (1993) Pharmacogenetics: its biologic roots and the medical challenge. Clin Phamacol Ther 54:235–241
Gu L, Gonzalez FJ, Kalow W, Tang BK (1992) Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 2:73–77
Lelo A, Miners JO, Robson RA, Birkett DJ (1986) Quantitative assessment of caffeine partial clearances in man. Br J Clin Pharmacol 22:183–186
Song BJ (1996) Ethanol-inducible cytochrome P450 (CYP2E1): biochemistry, molecular biology and clinical relevance: 1996 up-date. Alcohol Clin Exp Res 20:138–146
Alstott RL, Miller AJ, Forney RB (1973) Report of a human fatality due to caffeine. J Forensic Sci 18:135–137
Tanaka E, Nakamura T, Terada M, Shinozuka T, Honda K (2005) A study of the in vitro interaction between ethanol and triazolam and its two metabolites using human liver microsomes. J Clin Forensic Med 12:245–248
Tanaka E, Nakamura T, Terada M, Shinozuka T, Honda K (2005) Preliminary study of the in vitro interaction between alcohol, high-dose flunitrazepam and its three metabolites using human liver microsomes. Basic Clin Pharmacol Toxicol 96:88–90
Tanaka E, Nakamura T, Terada M, Shinozuka T, Honda K (2007) Metabolic interaction between ethanol, high-dose alprazoram and its two main metabolites using human liver microsomes in vitro. J Forensic Legal Med 14:348–351
Tanaka E, Nakamura T, Terada M, Honda K (2007) An in vitro study on the interaction between ethanol and imipramine at high concentrations using human liver microsomes. Forensic Toxicol 25:96–99
Wendt LR, Osvaldt AB, Bersch VP, Schumacher Rde C, Edelweiss MI, Rohde L (2007) Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine. Acta Cir Bras 22:202–209
Meneqaux F, Ripert M, He’mon D, Clavel J (2007) Maternal alcohol and coffee drinking, parental smoking and childhood leukaemia: a French population-based case-control study. Paediatr Perinat Epidemiol 21:293–299
Tworoger SS, Gertig DM, Gares MA, Hecht JL, Hankinson SE (2008) Caffeine, alcohol, smoking, and the risk of incident epithelial ovarian cancer. Cancer 112:1169–1177
Connole L, Harkin A, Maginn M (2004) Adenosine A1 receptor blockade mimics caffeine’s attenuation of ethanol-induced motor incoordination. Basic Clin Pharmacol Toxicol 95: 299–304
Martin FH, Garfield J (2006) Combined effects of alcohol and caffeine on the late components of the event-related potential and on reaction time. Biol Psychol 71:63–73
Roehrs T, Greenwald M, Roth T (2004) Risk-taking behavior: effects of ethanol, caffeine and basal sleepiness. Sleep 27: 887–893
Winek CL, Wahba WW, Winek CLJr, Balzer TW (2001) Drug and chemical blood-level data 2001. Forensic Sci Int 122:107–123
Rubin E, Gang H, Misra PS, Lieber CS (1970) Inhibition of drug metabolism by acute ethanol intoxication. A hepatic microsomal mechanism. Am J Med 49:801–806
Schüppel RV, Kuthe C (1980) Ethanol as a selective inhibitor of microsomal barbiturate hydroxylation in vitro and in vivo. Adv Exp Med Biol 132:363–372
Cinti DL, Grundin R, Orrenius S (1973) The effect of ethanol on drug oxidations in vitro and the significance of ethanol-cytochrome P-450 interaction. Biochem J 134:367–375
Mitchell MC, Hoyumpa AM, Schenker S, Johnson RF, Nichols S, Patwardhan RV (1983) Inhibition of caffeine elimination by short-term ethanol administration. J Lab Clin Med 101:826–834
Azona O, Barbanoj MJ, Torrent J, Jané F (1995) Evaluation of the central effect of alcohol and caffeine interaction. Br J Clin Pharmacol 40:393–400
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Nakamura, T., Tanaka, E. & Honda, K. An in vitro study on the metabolic interaction between ethanol and caffeine at high concentrations using human liver microsomes. Forensic Toxicol 27, 86–89 (2009). https://doi.org/10.1007/s11419-009-0068-z
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DOI: https://doi.org/10.1007/s11419-009-0068-z