Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women

Abstract

Purpose Cytochrome b5 (encoded by CYB5A) and NADH cytochrome b5 reductase (encoded by CYB5R3) detoxify aromatic and heterocyclic amine mammary carcinogens found in cigarette smoke. We hypothesized that CYB5A and CYB5R3 polymorphisms would be associated with breast cancer risk in women. Methods We characterized the prevalence of 18 CYB5A and CYB5R3 variants in genomic DNA from African American (AfrAm) and Caucasian (Cauc) women from the Carolina Breast Cancer Study population (1946 cases and 1747 controls), and determined their associations with breast cancer risk, with effect modification by smoking. Results A CYB5R3 variant, I1M+6T (rs8190370) was significantly more common in breast cancer cases (MAF 0.0238) compared to controls (0.0169, P =0.039); this was attributable to a higher MAF in AfrAm cases (0.0611) compared to AfrAm controls (0.0441, P=0.046; adjusted OR 1.41, CI 0.98-2.04; P=0.062). When smoking was considered, I1M+6T was more strongly associated with breast cancer risk in AfrAm smokers (adjusted OR 2.10, 1.08-4.07; P=0.028) compared to never-smokers (OR=1.21; 0.77-1.88; P for interaction=0.176). I1M+6T and three additional CYB5R3 variants, -251T, I8-1676C, and *392C, as well as two CYB5A variants, 13G and I2-992T, were significantly more common in AfrAms compared to Caucs. Conclusions CYB5R3 I1M+6 C>T should be considered in future molecular epidemiologic studies of breast cancer risk in AfrAms. Further, variants in CYB5A and CYB5R3 should be considered in the evaluation of other tumors in AfrAms that are associated with aromatic and heterocyclic amine exposures, to include prostate, bladder, and colon cancers.

The single nucleotide polymorphism and haplotype analysis of MDR1 in Chinese diffuse large B cell lymphoma patients

“…It 13 encodes a 170 kDa membrane transporter named P-glycoprotein 14 (P-gp), which is a member of the adenosine triphosphate (ATP) 15 binding cassette (ABC) transporter of the MDR/TAP subfamily and 16 is also called ATP-binding cassette subfamily B member 1 (ABCB1) 17 [1,2]. The P-gp is the first defence of the body against oral exposure 18 to drugs and toxins, reducing the intercellular concentrations of 19 different chemotherapeutic agents. Moreover, the MDR1 gene is 20 indicated highly polymorphic, and up to now a total of 50 MDR1 21 single nucleotide polymorphisms (SNPs) have been discovered 22 [2,3].…”

Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?

“…The purity of VDAC1 preparations studied usually reaches only 90-95%. In all cases, other proteins of equal molecular weights (32)(33)(34)(35) are present, which affect the efficiency of separation [15][16][17][18]. It was reported that Cyb5R3 consists of 5-10% of the purified VDAC1 [15,18].…”

“…Cyb5R3 is also recognized as a carcinogen detoxification gene [32,33], although its role in carcinogenesis is not yet well studied. Single reports on the role of OMM Cyb5R3 in cancer have appeared over the past 10 years [32,34,35].…”

“…Cyb5R3 is also recognized as a carcinogen detoxification gene [32,33], although its role in carcinogenesis is not yet well studied. Single reports on the role of OMM Cyb5R3 in cancer have appeared over the past 10 years [32,34,35]. It was found that the enzyme is overexpressed in cancer cells, protecting them against oxidative stress and induction of apoptosis [32,34,35].…”

“…Two groups have reported that membrane-bound Cyb5R3 overexpression and polymorphism are associated with breast cancer risk in women [32,34]. Blanke et al have found that one variant of Cyb5R3 is significantly overexpressed in African American women with breast cancer, which is accompanied by impaired detoxification of aromatic and heterocyclic amine mammary carcinogens in cigarette smoke [32]. The authors suggest that overexpression of membrane-bound Cyb5R3 should be considered as a valuable marker in etiologic studies of prostate, bladder, and colon cancers, which are also associated with exposure to arylamine and heterocyclic amine carcinogens.…”