Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas

被引:92
作者
Ishibe, N
Sinha, R
Hein, DW
Kulldorff, M
Strickland, P
Fretland, AJ
Chow, WH
Kadlubar, FF
Lang, NP
Rothman, N
机构
[1] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
[2] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA
[3] Univ Connecticut, Sch Med, Div Biostat, Dept Community Med & Hlth Care, Farmington, CT USA
[4] Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA
[5] Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA
来源
PHARMACOGENETICS | 2002年 / 12卷 / 02期
关键词
heterocyclic amines; MelQx; colorectal adenomas; N-acetyltransferases;
D O I
10.1097/00008571-200203000-00008
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MelQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68,95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1* 10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% Cl 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% Cl 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% Cl 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% Cl 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations.
引用
收藏
页码:145 / 150
页数:6
相关论文
共 64 条
[1]   A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene:: association with tardive dyskinesia in schizophrenia [J].
Basile, VS ;
Özdemir, V ;
Masellis, M ;
Walker, ML ;
Heltzer, HY ;
Lieberman, JA ;
Potkin, SG ;
Alva, G ;
Kalow, W ;
Macciardi, FM ;
Kennedy, JL .
MOLECULAR PSYCHIATRY, 2000, 5 (04) :410-417
[2]  
BELL DA, 1995, CANCER RES, V55, P3537
[3]  
BELL DA, 1995, CANCER RES, V55, P5226
[4]   GENOTYPE-PHENOTYPE DISCORDANCE FOR HUMAN ARYLAMINE N-ACETYLTRANSFERASE (NAT2) REVEALS A NEW SLOW-ACETYLATOR ALLELE COMMON IN AFRICAN-AMERICANS [J].
BELL, DA ;
TAYLOR, JA ;
BUTLER, MA ;
STEPHENS, EA ;
WIEST, J ;
BRUBAKER, LH ;
KADLUBAR, FF ;
LUCIER, GW .
CARCINOGENESIS, 1993, 14 (08) :1689-1692
[5]  
BOOBIS AR, 1994, CANCER RES, V54, P89
[6]   DETERMINATION OF CYP1A2 AND NAT2 PHENOTYPES IN HUMAN-POPULATIONS BY ANALYSIS OF CAFFEINE URINARY METABOLITES [J].
BUTLER, MA ;
LANG, NP ;
YOUNG, JF ;
CAPORASO, NE ;
VINEIS, P ;
HAYES, RB ;
TEITEL, CH ;
MASSENGILL, JP ;
LAWSEN, MF ;
KADLUBAR, FF .
PHARMACOGENETICS, 1992, 2 (03) :116-127
[7]  
Chen J, 1998, CANCER RES, V58, P3307
[8]  
Chevalier D, 2001, Hum Mutat, V17, P355, DOI 10.1002/humu.48
[9]   Detection of three genetic polymorphisms in the 5′-flanking region and intron 1 of human CYP1A2 in the Japanese population [J].
Chida, M ;
Yokoi, T ;
Fukui, T ;
Kinoshita, M ;
Yokota, J ;
Kamataki, T .
JAPANESE JOURNAL OF CANCER RESEARCH, 1999, 90 (09) :899-902
[10]  
CHOU HC, 1995, CANCER RES, V55, P525