Objective: The purpose of our study was to evaluate the evidence on the prevalence of cytochrome P450 enzyme polymorphisms as potential genetic factors influencing drug efficacy and safety in the indigenous populations of the American hemispheres. Methods: We conducted a systematic review of studies published between 1985 and 2006 using the Pubmed database. Results: We identified only 10 original research studies on CYP2A6, CYP2D6, CYP2C9, CYP2C19 and CYP2E1 in 13 indigenous American populations. Interethnic differences in the frequency of CYP450 genetic variants existed both among the examined indigenous populations and in comparison with African, Asian and European populations. Conclusions: There are surprisingly few data on CYP450 enzyme polymorphisms in indigenous American populations, and it is difficult to draw any clear inferences about how these populations might be expected to respond to drugs in relation to other racial or ethnic groups. This lack of information could create a barrier to the use of pharmacogenetic testing in these populations. Collaborative partnerships between indigenous communities and researchers are needed to avail the clinical benefits of CYP450 enzyme polymorphism testing to indigenous populations.

Keywords:
Indigenous Americans, Pharmacogenetics, Drug metabolizing enzymes, Cytochrome P450, Allele frequency
1.
Gardiner SJ, Begg EJ: Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006;58:521–590.
2.
Tate SK, Goldstein DB: Will tomorrow’s medicines work for everyone? Nat Genet 2004;36:S34–S42.
3.
Daly AK: Pharmacogenetics of the cytochromes P450. Curr Top Med Chem 2005;5:1733–1744.
4.
Ma MK, Woo MH, McLeod H: Genetic basis of drug metabolism. Am J Health Syst Pharm 2002;59:2061–2069.
5.
Fisbain DA, Fisbain D, Lewis J, Cutler RB, Cole B, Rosomoff HL, Rosomoff RS: Genetic testing for enzymes of drug metabolism: does it have clinical utility for pain medicine at the present time? A structured review. Pain Med 2004;5:81–93.
6.
Nebert DW, Russell DW: Clinical importance of the cytochromes P450. Lancet 2002;360:1155–1162.
7.
Daly AK: Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 2003;17:27–41.
8.
De Leon J, Susce MT, Murray-Carmichael E: The Amplichip CYP450 genotyping test: integrating a new clinical tool. Mol Diagn Ther 2006;10:135–151.
9.
Montenegro RA, Stephens C: Indigenous health. 2. Indigenous health in Latin America and the Caribbean. Lancet 2006;367:1859–1869.
10.
Lillie-Blanton M, Roubideaux Y: Understanding and addressing the health care needs of the American Indians and Alaskan Natives. Am J Public Health 2005;95:759–761.
11.
Sharp RR, Foster M: Community involvement in the ethical review of genetic research: lessons from American Indians and Alaskan Native populations. Environ Health Perspect 2002;110(suppl 2):145–148.
12.
Weijer C, Miller PB: Protecting communities in pharmacogenetics and pharmacogenomics research. Pharmacogenomics J 2004;4:9–16.
13.
Weijer C, Emanuel EJ: Protecting communities in biomedical research. Science 2000;289:1142–1144.
14.
Smith LT: Decolonizing Methodologies: Research and Indigenous People. Dunedin, University of Otago Press, 1999.
15.
Arbour L, Cook D: DNA on loan: issues to consider when carrying out genetic research with aboriginal families and communities. Community Genet 2006;9:153–160.
16.
Kircheiner J, Brockmoller J: Clinical consequences of cytochrome P4502C9 polymorphisms. Clin Pharmacol Ther 2005;77:1–16.
17.
Sanderson S, Emery J, Higgins J: CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005;2:97–104.
18.
Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE: Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002;287:1690–1698.
19.
Nasu K, Kubota T, Ishizaki T: Genetic analysis of CYP2C9 polymorphisms in a Japanese population. Pharmacogenetics 1997;7:405–409.
20.
Wang SL, Huang J, Lai MD, Tsai JJ: Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 1995;5:37–42.
21.
Gaedigk A, Casley WL, Tyndale RF, Sellers EM, Jurima-Romet M, Leeder JS: Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations. Can J Physiol Pharmacol 2001;79:841–847.
22.
Dickmann LJ, Rettie AE, Kneller B, Kim R, Wood AJ, Stein CM, Wilkinson GR, Schwarz UI: Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 2001;60:382–387.
23.
Llerena A, Dorado P, O’Kirwan, Jepson R, Licinio J, Wong M-L: Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards. Pharmacogenomics J 2004;4:403–406.
24.
Stubbins MJ, Harris LW, Smith G, Tarbit MH, Wolf CR: Genetic analysis of the human cytochrome P-450 CYP2C9 locus. Pharmacogenetics 1996;2:429–439.
25.
Nowak MP, Sellers EM, Tyndale RF: Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies. Clin Pharmacol Ther 1998;64:378–383.
26.
Jurima-Romet M, Goldstein JA, LeBelle M, Aubin RA, Foster BC, Walop W, Rode A: CYP2C19 genotyping and associated mephenytoin hydroxylation polymorphism in a Canadian Inuit population. Pharmacogenetics 1996;6:329–339.
27.
Yamada S, Onda M, Kata S, Matsuda N, Yamada N, Miki M, Matsukura N: Genetics differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J Gastroenterol 2001;36:669–672.
28.
Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA: Frequencies of the defective CYP2C19 alleles responsible for the mephanytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 1997;7:59–64.
29.
Desta Z, Zhao X-J, Shin J-G, Flockhart D: Clinical significance of the cytochrome P450 2C19 genetic polymorphisms. Clin Pharmacokinet 2002;41:913–958.
30.
Takakubo F, Kuwano A, Kondo I: Evidence that poor metabolizers of (S)-mephenytoin could be identified by haplotypes of CYP2C19 in Japanese. Pharmacogenetics 1996;6:265–267.
31.
Zanger UM, Raimundo S, Eichelbaum M: Cytochrome P450: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369:23–37.
32.
Bradford DL: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics J 2002;3:229–243.
33.
Nowak MP, Tyndale RF, Sellers EM: CYP2D6 phenotype and genotype in a Canadian Native Indian population. Pharmacogenetics 1997;7:145–148.
34.
Jurima-Romet M, Foster BC, Casley WL, Rode A, Vloshinsky P, Huang HS, Geertsen S: CYP2D6-related oxidation polymorphism in a Canadian Inuit population. Can J Physiol Pharmacol 1997;75:165–172.
35.
Jorge LF, Eichelbaum M, Griese E, Inaba T, Arias TD: Comparative evolutionary pharmacogenetics of CYP2D6 in Ngawbe and Embera Amerindians of Panama and Colombia: role of selection versus drift in world population. Pharmacogenetics 1999;9:217–228.
36.
Munoz S, Vollrath V, Vallejos MP, Miquel JF, Covarrubias C, Raddatz A, Chianale J: Genetic polymorphisms of CYP2D6, CYP1A1 and CYP 2E1 in the South-Amerindian population of Chile. Pharmacogenetics 1998;8:343–351.
37.
Sosa-Macias M, Elizondo G, Flores-Perez C, Flores–Perez J, Bradley-Alvarez F, Alanis-Banuelos RE, Lares-Asseff I: CYP2D6 genotype and phenotype in Amerindians of Tepehuano origin and Mestizos of Durango, Mexico. J Clin Pharmacol 2006;46:527–536.
38.
Nishida Y, Fukuda T, Yamamoto I, Azuma J: CYP2D6 genotypes in a Japanese population: low frequencies of CYP2D6 gene duplication but high frequency of CYP2D6*10. Pharmacogenetics 2000;10:567–570.
39.
Gaedigk A, Gotschall RR, Forbes NS, Simon SD, Kearns GL, Leeder JS: Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data. Pharmacogenetics 1999;9:1–15.
40.
Casner PR: The effects of CYP2D6 polymorphisms on dextromethorphan metabolism in Mexican Americans. J Clin Pharmacol 2005;45:1230–1235.
41.
Aklillu E, Herrlin K, Gustafsson LL, Bertilsson L, Ingelman-Sundberg M: Evidence for environment influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics 2002;12:375–383.
42.
Rautio A: Polymorphic CYP2A6 and its clinical and toxicological significance. Pharmacogenomics J 2003;3:5–7.
43.
Xu C, Rao YS, Xu B, Hoffmann E, Jones J, Seller EM, Tyndale RF: An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochem Biophys Res Commun 2002;290:318–324.
44.
Yoshida R, Nakajima M, Watanabe Y, Kwon JT, Yokoi T: Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br J Clin Pharmacol 2002;54:511–517.
45.
Nurfadhlina M, Foong K, Teh LK, Tan SC, Mohdzaki S, Ismail R: CYP2A6 polymorphisms in Malays, Chinese and Indians. Xenobiotica 2006;36:684–692.
46.
Schoedel KA, Hoffmann EB, Rao Y, Seller EM, Tyndale RF: Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 2004;14:615–626.
47.
Garte S, Gaspari L, Alexandrie A-K, Ambrosone C, Autrup H, Autrup JI, Baranova H, Bathum L, Benhamou S, Boffetta P, Bouchardy C, Breskvar K, Brockmöller J, Cascorbi I, Clapper ML, Coutelle C, Daly A, Dell’Omo M, Dolzana V, Dresler CM, Fryer A, Haugen A, Hein DW, Hildesheim A, Hirvonen A, Hsich L-L, Ingelman-Sundberg M, Kalina I, Kang D, Kihara M, Kiyohara C, Kremers P, Lazarus P, Le Marchand L, Lechner MC, Lieshout EMM, London S, Manni JJ, Maugard CM, Morita S, Nazar-Stewart V, Noda K, Oda Y, Parl FF, Pastorelli R, Persson I, Peters WHM, Rannug A, Rebbeck T, Risch A, Roelandt L, Romkes M, Ryberg D, Salagovic J, Schoket B, Seidegard J, Shileds PG, Sim E, Sinhet D, Strange RC, Stücker I, Sugimura H, To-Figueras J, Vineis P, Yu MC, Taioli E: Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001;10:1239–1248.
48.
Mendoza-Cantu A, Castorena-Torres F, Bermudez M, Martinez-Hernandez R, Ortega A, Salinas JE, Albores A: Genotype and allele frequencies of polymorphic cytochromes P450 CYP1A2 and CYP2E1 in Mexicans. Cell Biochem Funct 2004;22:29–34.
49.
Stephens EA, Taylor JA, Kaplan N, Yang CH, Hsieh LL, Lucier GW, Bell DA: Ethnic variation in the CYP2E1 gene: polymorphism analysis of 695 African-Americans, European-Americans and Taiwanese. Pharmacogenetics 1994;4:185–192.
50.
Gasper PA, Hutz MH, Salzano FM, Hill K, Hurtado AM, Petzl-Erler ML, Tsuneto LT, Weimer TA: Polymorphisms of CYP1A1, CYP2E1, GSTM1, GSTT1 and TP53 in Amerindians. Am J Phys Anthropol 2002;119:249–256.
51.
Watanabe J, Hayashi S-I, Nakachi K, Imai K, Suda Y, Sekine T, Kawajiri K: Pst I and Rsa I RFLPs in complete linkage disequilibrium at the CYP2E gene. Nucleic Acids Res 1990;18:7194.
52.
Chao Y-C, Young T-H, Chang W-K, Tang H-S, Hsu C-T: An investigation into whether polymorphisms of cytochrome P4502E1 are genetic markers of susceptibility to alcoholic end-stage organ damage in Chinese populations. Hepatology 1995;22:1409–1414.
53.
Suarez-Kurtz G: Pharmacogenomics in admixed populations. Trends Pharmacol Sci 2005;26:196–201.
© 2008 S. Karger AG, Basel
2008
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.