Skip to main content
SpringerLink
Log in

Determination of N-acetylation phenotyping in a greek population using caffeine as a metabolic probe

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

Studies of isoniazid, the well known antituberculosis drug, have revealed that N-acetylation polymorphism, is of great clinical importance. In human, N-acetylation is one of the most important pathways in the inactivation of isoniazid. Caffeine, which is also biotransformed by N-acetylation, has been widely used as anin vivo probe for the assessment of N-acetyltransferase polymorphism. The activity of N-acetyltransferase can be estimated from the urinary metabolic ratio of two caffeine metabolites, namely, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), and 1-methylxathine (1X) after the ingestion of caffeine.

In the present study caffeine was used as a metabolic probe to determine N-acetyltransferase polymorpism in 83 healthy Greek volunteers by means of the molar ratio of AFMU and 1X determined in urine following ingestion of 200 mg caffeine. Frequency distribution analysis of the metabolic ratios AFMU/1X revealed two distinct groups with 66.3% (n=55) slow acetylators and 33.7% (n=28) rapid acetylators. No statistically significant difference was detected between slow and fast acetylators in terms of gender, smoking habits and caffeine-intake habits. These results are in agreement with previous studies on N-acetyltransferase activity in Caucasians using caffeine as a metabolic probe. They also agree with reports on N-acetyltransferase activity in Greek tuberculosis patients using isoniazid as a metabolic probe. Thus, the use of caffeine as a metabolic probe is a reliable method for the assessment of N-acetyltransferase activity in the Greek population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Evans D.A.P., Manley F.A., and McKusick V.A. (1960): Genetic control of isoniazid metabolism in man. Br. Med. J., 2, 485–491.

    Article  PubMed  CAS  Google Scholar 

  2. Blum M., Grant D.M., Demierre A., and Meyer U.A. (1989): N-Acetylation pharmacogenetics: A gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits. Proc. Natl. Acad. Sci. USA, 86, 9554–9557.

    Article  PubMed  CAS  Google Scholar 

  3. Blum M., Grant D.M., McBride W., Heim M., and Meyer U.A. (1990): Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol., 9, 193–203.

    Article  PubMed  CAS  Google Scholar 

  4. Peters J.H., Miller K.S., and Brown P. (1965) The determination of isoniazid and its metabolites in human urine. Anal. Biochem., 12, 379–394.

    Article  PubMed  CAS  Google Scholar 

  5. Mitchell J.R., Thorgeirsson U.P., Black M., Timbrell J.A., Snodgrass W.R., Potter W.Z., Jollow D.J., and Kaiser H.R. (1975): Increased incidence of isoniazid hepatitis in rapid acetylators: Possible relation to hydrazine metabolites. Clin. Pharmacol. Ther. 18, 70–79.

    PubMed  CAS  Google Scholar 

  6. Ellard G.A., and Gammon P.T. (1976): Pharmacokinetics of isoniazid metabolism in man. J. Pharmacokinet. Biopharm., 4, 83–113.

    Article  PubMed  CAS  Google Scholar 

  7. Hyman C.L. (1995): Tuberculosis: a survey and review of the current literature. Curr. Opin. Pulm. Med., 1, 234–242.

    PubMed  CAS  Google Scholar 

  8. Valway S.E., Sanchez M.P., Shinnick T.F., Orme I., Agerton T., Hoy D., Jones J.S., Westmoreland H., and Onorato I.M. (1998): An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N. Engl. J. Med., 338, 633–639.

    Article  PubMed  CAS  Google Scholar 

  9. Curatolo P.W., and Robertson D. (1986): The health consequences of caffeine. Ann. Intern. Med., 98, 641–653.

    Google Scholar 

  10. Grant D.M., Tang B.K., and Kalow W. (1983): Variability in caffeine metabolism. Clin. Pharmacol. Ther., 33, 591–602.

    PubMed  CAS  Google Scholar 

  11. Tang B.K., Grant D.M., and Kalow W. (1983): Isolation and identification of 5-acetylamino-6-formylamino-3-methyluracil as a major metabolite of caffeine in man. Drug Metab. Dispos., 11, 218–220.

    PubMed  CAS  Google Scholar 

  12. Grant D.M., Tang B.K., and Kalow W. (1984): A simple test for acetylatror phenotype using caffeine. Br. J. Clin. Pharmacol., 17, 459–464.

    PubMed  CAS  Google Scholar 

  13. MacLean, C.J., Morton N.E., Elston R.C., and Yee S. (1976): Skewness in commingled distributions. Biometrics, 32, 695–699.

    Article  PubMed  CAS  Google Scholar 

  14. Mead R. (1990): The design of experiments. Cambridge.

  15. McCullagh P., and Nelder J.A. (1989): Generalized linear models. London: Chapman and Hall.

    Google Scholar 

  16. Pontes Z.B., Vincent-Viry M., Gueguen R., Galteau M.M., and Siest G. (1993): Acetylation phenotypes and biological variation in a French Caucasian population. Eur. J. Clin. Chem. Clin. Biochem., 31, 59–68.

    PubMed  CAS  Google Scholar 

  17. Tang B.K., Kadar D., Qian L., Iriah J., Yip J., and Kalow W. (1991): Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. Clin. Pharmacol. Ther., 49, 648–657.

    PubMed  CAS  Google Scholar 

  18. Cascorbi I., Drakoulis N., Brockmoller J., Maurer A., Sperling K., and Roots I. (1995): Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: correlation with phenotypic activity. Am. J. Hum. Genet., 57, 581–592.

    PubMed  CAS  Google Scholar 

  19. Ou-Yang D.-S., Huang S.-L., Xie H.-G., Wang C.-Y., and Zhou H.-H. (1998): Use of caffeine as a probe for rapid determination of cytochrome P-450 CYP1A2 activity in humans. Acta Pharmacol. Sinica, 19, 44–46.

    CAS  Google Scholar 

  20. Kottakis I. (1992): Phenotypes of isoniazid metabolism in Greece. Ph.D. Thesis, Medical School, University of Athens, Greece.

    Google Scholar 

  21. Hickman D., and Sim E. (1991): N-acetyltransferase polymorphism: comparison of phenotype and genotype in humans. Biochem. Pharmacol., 42, 1007–1014.

    Article  PubMed  CAS  Google Scholar 

  22. Graf T., Broly F., Hoffman F., Probst M., Meyer U.A., and Howland H. (1992): Prediction of phenotype for acetylation and for debresoquine hydroxylation by DNA-tests in healthy human volunteers. Eur. J. Clin. Pharmacol., 43, 399–403.

    Article  PubMed  CAS  Google Scholar 

  23. Iselius L., and Evans D.A.P. Formal genetics of isoniazid metabolism in man. Clin. Pharmacokinet. 8, 541–544, 1983.

    Article  PubMed  CAS  Google Scholar 

  24. Rasmussen B.B., Brosen K. (1996): Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activity in humans. Ther. Drug Monit., 18, 254–262.

    Article  PubMed  CAS  Google Scholar 

  25. Campbell M.E., Spielberg S.P., and Kalow W. (1987): A urinary metabolic ratio that reflects systemic caffeine clearence. Clin. Pharmacol. Ther., 42, 157–165.

    PubMed  CAS  Google Scholar 

  26. Lu J.F., Yi T., Cao X.M., Zhuo H.T., and Ling S.S. (1997): Determination of caffeine metabolite for the evaluation of N-acetyltransferase, CYP1A2 and xanthine oxidase activities. Acta Pharm. Sinica, 32, 813–818.

    CAS  Google Scholar 

  27. Kalow W., and Tang B.K. (1991): Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin. Pharmacol. Ther., 49, 44–48.

    PubMed  CAS  Google Scholar 

  28. West R.W., and Thompson J.R. (1997): Modeling the impact of HIV on the spread of tuberculosis in the United States. Math. Biosci., 143, 35–60.

    Article  PubMed  CAS  Google Scholar 

  29. Ridson R., Kent J.H., Valway S., Weismuller P., Maxwell R., Elcock M., Meador J., Royce S., Shefer A., Smith P., Woodley C., and Onorato I. (1997): Outbreak of drug-resistant tuberculosis with second-generation transmission in a high school in California. J. Pediatr., 131, 863–868.

    Article  Google Scholar 

  30. Harries A.D., Parry C., Nyongonya Mbewe L., Graham S.M., Daley H.M., Maher D., Salaniponi F.M., and Nyangulu D.S. (1997): The pattern of tuberculosis in Queen Elizabeth Central Hospital, Blantyre, Malawi: 1986–1995. Int. J. Tuberc. Lung Dis., 1, 346–351.

    PubMed  CAS  Google Scholar 

  31. Vineis P., Bartsch H., Caporaso N., Harrington A.M., Kadlubar F.F., Landi M.T., Malaveille C., Shields P.G., Skipper P., Talaska G., and Tannenbaum S.R. (1994): Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature, 369, 154–156.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Pharmacology, Department of Medicine, University of Thessalia, Larissa, Greece

    E. K. Asprodini, E. Zifa, I. Papageorgiou & A. Benakis

Authors
  1. E. K. Asprodini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Zifa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Papageorgiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Benakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Asprodini, E.K., Zifa, E., Papageorgiou, I. et al. Determination of N-acetylation phenotyping in a greek population using caffeine as a metabolic probe. Eur. J. Drug Metab. Pharmacokinet. 23, 501–506 (1998). https://doi.org/10.1007/BF03190002

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03190002

Keywords

Search

Navigation