Abstract
The aim of the present study was to evaluate the relative contribution of CYP1A2 isoforms (-3860 G/A, -2467T/delT and -163C/A) in control subjects and breast cancer patients to the metabolism of caffeine in human liver. Restriction fragment length polymorphism analysis of PCR-amplified Fragments (PCR-RFLP) was used for the genotyping of CYP1A2 SNPs and HPLC allowed the phenotyping through the measurement of CYP1A2 activity using the 17X + 13X + 37X/137X urinary metabolite ratio (CMR) and plasma caffeine half life (T1/2). The CYP1A2 -3860A genotype was associated with a decreased risk of breast cancer. In contrast, distributions of the CYP1A2 -2467T/delT or -2467delT/delT and -163A/C or A/A genotypes among breast cancer patients and controls were similar. When the genotype and phenotype relationship was measured by comparing the mean CMR ratios and caffeine half life within the genotype groups between subjects and breast cancer patients, there were no significant differences except for -3860 A, most of them being homozygous for the -3860 G/G SNP and had a significant higher mean CMR ratio and half life than those with -3860 G/A (P=0.02). The results of this preliminary study show a significant association between CP1A2 -3860 G variant and CYP1A2 phenotype which must be confirmed by further large-size case-control studies.
Highlights
Breast cancer is the most common malignant tumor in women in both developed and developing countries
When the genotype and phenotype relationship was measured by comparing the mean caffeine metabolic ratio (CMR) ratios and caffeine half life within the genotype groups between subjects and breast cancer patients, there were no significant differences except for -3860 A, most of them being homozygous for the -3860 G/G SNP and had a significant higher mean CMR ratio and half life than those with -3860 G/A (P=0.02)
Statistical comparisons of CMR mean value: Mann–Whitney U-test,*CYP1A2 −163 C/C vs −163 C/A or A/A p
Summary
Breast cancer is the most common malignant tumor in women in both developed and developing countries. Epidemiological studies have shown that prolonged exposure to estrogens, 17 β-estradiol (E2), is one of the primary risk factors for the development of tumors such as breast cancer tumors (Evans et al, 2003) and genes involved in estrogen metabolism have been reported to mediate that risk (Rebbeck et al, 2007). Significant effects of heritable factors were observed for breast cancers in a large study of twins performed in three Nordic countries environment has the predominant role (Ahlbom et al, 1997; Lichtenstein et al., 2000). Frequent consumption of well-done meat that contains heterocyclic aromatic amines has been reported to elevate the risk of developing human cancers including breast cancers (Zheng et al, 1998; Hein et al, 2000; Williams and Phillips, 2000; DeBruin and Josephy, 2002; Turesky 2004). Increased activity of CYP1A2 has been associated with increased risks of breast cancer in some studies (Hong et al, 2004; Le Marchand, 2005; Shimada et al, 2009; Sangrajrang et al, 2009; Chang-Claude et al, 2010; Khvostova et al, 2012) while a number of other studies investigating the potential associations between CYP1A2 polymorphism and cancer risk have been inconsistent (Agundez, 2004; Long et al, 2007; Qiu et al, 2010; Singh et al, 2011; Lee et al, 2013)
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