Clin Chem Lab Med 2002; 40(9):952–957 © 2002 by Walter de Gruyter · Berlin · New York Collet Dandara 1 *, Jane Sayi 2 , Collen M. Masimirembwa 1 , Ayoub Magimba 2 , Sylvia Kaaya 2 , Klerk De Sommers 3 , Jacques René Snyman 3 and Julia A. Hasler 1 1 Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe 2 Department of Pharmacology, Muhimbili College of Health Sciences, Dar es Salaam, Tanzania 3 Department of Pharmacology, University of Pretoria, South Africa The co-ordinate expression and regulation of the drug metabolising enzymes, cytochrome P4501A1 (CYP1A1) and glutathione transferases (GSTM1, GSTT1 and GSTP1), and their metabolic balance in the cells of tar- get organs may determine whether exposure to car- cinogens results in cancer. Besides showing variability in activity due to induction and inhibition, these en- zymes also exhibit genetic polymorphism that alter en- zyme levels and activity. We determined frequencies of common allelic variants of CYP1A1 and glutathione (M1, T1 and P1) among Tanzanians, South African Venda and Zimbabweans using PCR/restriction frag- ment length polymorphism techniques. The CYP1A1 Val 462 mutant variant was found at a frequency of 1.3% among 114 subjects. The GSTM1*0 genotype was found at a frequency of 29% and 33% among Tanzanian psychiatric patients and healthy volunteers, respec- tively. Similarly, the GSTT1*0 polymorphism was pre- sent with a frequency of 25% in both the psychiatric pa- tients and healthy controls. The frequency of GSTP1 Val 105 variant was 16%, 12% and 21% among Tanzani- ans, South African Venda and Zimbabweans, respec- tively. We conclude here that CYP1A1 Val 462 polymor- phism is very rare among Africans. This is the first report of the GSTP1 Val 105 variant frequency in African populations. We show here that there are no differ- ences in frequencies of the variant alleles for CYP1A1, GSTM1, GSTT1 and GSTP1 in the three African popula- tions. Clin Chem Lab Med 2002; 40(9):952–957 Key words: Gene polymorphism; Africans; Cyto- chrome P450; Glutathione transferase. Abbreviations: AFB 1 , aflatoxin B1; CYP, cytochrome P450; GST, glutathione transferase; HCC, hepatocellu- lar carcinoma; Ile, isoleucine; PCR, polymerase chain reaction; RFLP, restriction fragment length polymor- phism; SNPs, single nucleotide polymorphisms; UV, ul- traviolet. Introduction Drug metabolising enzymes have been implicated in carcinogenesis through bioactivation of procarcino- gens to reactive metabolites (1). Depending on the metabolic pathway and enzyme involved, biotransfor- mation can result in the production of genotoxic inter- mediates or in the detoxification of the carcinogens (2). The co-ordinate expression and regulation of the drug metabolising enzymes cytochrome P4501A1 (CYP1A1) and glutathione transferases (GSTM1, GSTT1 and GSTP1) and their metabolic balance in the cells of tar- get organs may determine whether exposure to car- cinogens results in cancer or not (3–5). Besides regula- tion of enzyme activity through induction and inhibition (6), allelic variants exist which alter enzyme activity. The CYP1A1, GSTT1, GSTM1 and GSTP1 genes are polymorphic, and a proportion of the population ex- hibits deficient, reduced or enhanced activity of a spe- cific enzyme (7). This genetic variability is the basis of interindividual and interethnic differences observed in the activity of these enzymes in Oriental and Caucasian populations (8, 9). Many aromatic aryl hydrocarbons, such as benzo(a)- pyrene found in cigarette smoke require metabolic ac- tivation by CYP1A1 to their ultimate DNA-binding mu- tagenic form (10). Increased susceptibility to lung cancer has been associated with two mutually linked polymorphisms (MspI polymorphism and Ile 462 to Val 462 change) of the CYP1A1 gene in Japanese popula- tions (11). In yeast, heterologously expressed CYP1A1 Val 462 variant had 2-fold higher activity compared to the CYP1A1 Ile 462 for benzo(a)pyrene metabolism (12). Aflatoxin B 1 is bioactivated to a hepatocarcinogenic epoxide by CYP1A2 (13), whilst benzopyrene is metabolised to a lung carcinogen by CYP1A1 (3). Glu- tathione S-transferases are part of the cellular detoxifi- cation machinery. These cytosolic enzymes generally inactivate electrophilic compounds (14), though some- times the conjugative reactions lead to the production of toxic metabolites (15). Several polymorphisms have been discovered in this supergene family of enzymes, and these include the deletions of GSTM1 and GSTT1 and two single nucleotide polymorphisms (SNPs) in GSTP1. The latter polymorphism results in variability in the catalytic efficiency of the affected enzyme (16–18), whilst the deletion of the GSTM1 and GSTT1 genes leads to a lack of the enzyme. Some studies have shown that individuals homozy- gous for GSTM1*0 are at greater risk of developing bladder and larynx cancer (19). A combination of CYP1A1 Val 462 and the GSTMI*0 genotypes has been *E-mail of the corresponding author: collet@xenobiot.icon.co.zw Genetic Polymorphism of Cytochrome P450 1A1 (CYP1A1) and Glutathione Transferases (M1, T1 and P1) among Africans Brought to you by | University of California - San Francisco Authenticated Download Date | 12/15/14 6:31 PM