Abstract Background: The typical U.S. diet is characterized by high carbohydrate intake, and dietary carbohydrates can modulate insulin sensitivity depending on their glycemic effect. Glycemic load and glycemic index, which represent the quality and quantity of carbohydrate foods, and prostate cancer risk are poorly characterized. Objective: To examine the association between dietary carbohydrate intake, glycemic load, and glycemic index and risk of prostate cancer, and determine if these associations differ between Whites and Blacks. Methods: We analyzed data from an ongoing case-control study of White (N=109) and Black (N=143) veterans at the Durham VA Medical Center. Cases were 65 men with biopsy-confirmed prostate cancer. There were two groups of controls: biopsy-negative controls (N=89) and healthy (i.e. no biopsy indication) controls (N=98). All men had a PSA test done in the year prior to enrolling in the study. Demographic and lifestyle risk factors were collected using self-administered questionnaires. Diet information was obtained using the Harvard food frequency questionnaire. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for prostate cancer risk were obtained using logistic regression analyses adjusted for age, race, and total energy. Results: Mean carbohydrate intake, glycemic load, and glycemic index were similar among cases and both groups of controls (all p-values >0.05). We did not observe any statistically significant risk estimates for high (≥median) carbohydrate intake, glycemic load, or glycemic index. Compared to healthy controls, the ORs for prostate cancer risk associated with high carbohydrate intake, glycemic load, and glycemic index were 0.66 (95% CI 0.34-1.30), 0.57 (95% CI 0.22-1.49), and 1.18 (95% CI 0.61-2.02) respectively. Corresponding ORs when compared to biopsy-negative controls were 0.88 (95% CI 0.46-1.70), 0.69 (95% CI 0.29-1.64), and 0.83 (95% CI 0.43-1.59), respectively. The associations between carbohydrate intake, glycemic load, or glycemic index and risk of low-grade (gleason score <7) as well as high-grade (gleason score ≥7) prostate cancer relative to healthy controls were null for all analyses. There was no evidence of effect modification by race in our analyses. Additional adjustment for fiber intake did not appreciably alter any of the ORs. Conclusion: Our findings in a small case-control study do not suggest that a high carbohydrate intake and/or high glycemic load increase the risk of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2826.
Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumor risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signaling pathways to also affect prostate tumor progression and is additionally associated with decreased DNA methylation. The expression of UGT2B15, UGT2B17, de novo methyltransferases, DNMT3A and DNMT3B was assessed in prostate cancer cells (LNCaP) treated with EGF; an EGFR inhibitor PD16893 and the methyltransferase inhibitor, 5-azacytidine, respectively. The results showed that EGF treatment decreased levels of expression for all four genes and that expression was reversed by PD16893. Treatment with 5- azacytidine, markedly decreased expression of UGT2B15 and UGT2B17 over 85% as well as significantly decreased expression of DNMT3B, but not the expression of DNMT3A. DNMT3B siRNA treated LNCaP cells had decreased expression for UGT2B15 and UGT2B17, while DNMT3A siRNA treated cells only moderately decreased UGT2B15 expression. Treatment with DNMT methyltransferase inhibitor, RG108 significantly decreased UGT2B17 expression. Additionally, methylation differences between prostate cancer samples and benign prostate samples from an Illumina 450K Methylation Array study were assessed. The results taken together suggest that hypomethylation of the UGT2B15 and UGT2B17 genes contributes to increased risk of prostate cancer and may provide a putative biomarker or epigenetic target for chemotherapeutics. Mechanistic studies are warranted to determine the role of the methylation marks in prostate cancer.
Abstract Background We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies. Methods Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis -acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk. Results After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis -acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100. Conclusions Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required.
We thank Drs. Wang and King for their interest in our article on NAT2 acetylation and bladder cancer risk in workers exposed to benzidine.1 In their letter to the editor,2 Drs. Wang and King indicated that our results contradict the conclusion reached by Cartwright et al.3 As we noted in our article,1 the apparent contradiction is explainable, at least in part, by the fact that workers in that report are likely to have been exposed to 2-naphthylamine, a monoarylamine, as well as to benzidine, a diarylamine (unpublished findings).3 In contrast, workers in the factories we studied were exposed primarily to benzidine and related compounds.1 Cartwright et al. were aware of the implications of studying NAT2 acetylation and bladder cancer among workers exposed to more than one aromatic amine, as they noted in their initial report that “…different aromatic amines have different activation pathways despite close molecular similarities.”3 Drs. Wang and King question our comments on the role of peroxidatic activity of prostaglandin H synthase (PHS) in benzidine carcinogenesis. They state that mono N-acetylation of benzidine effectively precludes the activation of benzidine by PHS. However, Zenser and colleagues have demonstrated that the peroxidatic activity of PHS converts N-acetylbenzidine (ABZ) to N′-hydroxy-N-acetylbenzidine (N'HA)4 and that in the presence of dGMP N′-(3′-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ) is formed.5 Drs. Wang and King have suggested that N′-hydroxy-N′-glucuronide-N-acetylbenzidine is likely to play a central role in benzidine bladder carcinogenesis, based on their findings in the rat heterotopic bladder model.6 Rothman et al.7 demonstrated that acidic urine pH increased the level of both free ABZ and the dGp-ABZ adduct in exfoliated urothelial cells of workers exposed to benzidine and benzidine-based dyes, and that ABZ strongly correlated with adduct levels. These observations are consistent with the hypothesis that N-acetylbenzidine-glucuronide may have an important role in benzidine carcinogenesis, as Zenser et al. have shown that this compound is extremely acid labile with its half-life reduced to several minutes under acidic conditions in urine.8, 9 In contrast, it is unlikely that DNA adduct formation would have been influenced by urine acidity if N′OHN-acetylbenzidine-N′-glucuronide was the only adduct forming agent, because this glucuronide is much more stable under acidic pH conditions, with a long half-life.8, 9 As such, the observations of Drs. Wang and King, based on the heterotopic bladder model, may not be generalizable, as this model does not mimic urine flow and urine pH, key components of aromatic amine carcinogenesis in human [a substantial proportion of humans have urine pH at or below pH 6.0 (N. Rothman, unpublished data)].10 Also, the lower relative carcinogenicity of N′-hydroxy-N-acetylbenzidine in this model may be explained by the relatively high pH (7.1–7.4) of the fluid in the heterotopic bladder, conditions under which N-hydroxy arylamines are known to be unstable. In addition, N′-hydroxy-N-acetylbenzidine itself may be excreted unconjugated in urine and it is known to react rapidly with DNA at acidic pH to form dGp-ABZ (this is how this adduct was originally characterized).11 Thus, N′-hydroxy-N-acetylbenzidine could be formed not only from PHS but also in liver from ABZ metabolism, then enter the circulation, and be filtered into the urinary bladder lumen, where it could be rapidly absorbed and further activated by NAT1 in the urinary bladder epithelium. Accordingly, we agree with Drs. Wang and King that other enzyme systems may also contribute to N-acetylbenzidine carcinogenicity and that it is possible that N′-hydroxy-N-acetylbenzidine can lead to bladder carcinogenesis through the formation of an N′-acetoxy ester. Thus, Figure 2 in our article, which summarized and compared key pathways in the metabolism of monoarylamines and diarylamines, has been revised as shown in Figure 1. Comparison of key pathways in the metabolism of monoarylamines and diarylamines. CYP1A1/CYP1A2, cytochrome P-450 1A1/1A2; NAT1/NAT2, N-acetyltransferase 1/2; UGT, UDP-glucuronosyltransferase; PHS, prostaglandin H-synthase. We would like to respond to their comment that we failed to report the identification of N′-hydroxy-acetylbenzidine-N′-glucuronide in human urine. Our study was an observational case-control study of bladder cancer patients and controls, who had worked previously in factories where benzidine was present but who were not exposed to benzidine at the time of our study; therefore, benzidine metabolites would not have been present in their urine.1 The Rothman et al. study7 enrolled workers exposed to benzidine and benzidine-based dyes at the time of the study and measured benzidine, and mono- and diacetylated benzidine, but did not measure N′-hydroxy-N′-acetylbenzidine-glucuronide. We agree that analysis of additional benzidine metabolites and their respective glucuronides, and the exploration of their correlation with DNA adducts in this study, would have been of interest, although as pointed out by Drs. Wang and King, some of these compounds may be so unstable that it is not feasible to measure them. The Rothman et al. analysis of benzidine, ABZ and DABZ before and after acid treatment provided an indirect measurement of the N-glucuronides of benzidine and ABZ, demonstrating their importance and presence in vivo.7 We agree with Drs. Wang and King's statement that benzidine and monoamino aromatics may be carcinogenic through similar pathways. Published evidence12, 13, 14 suggests that the second amino group of benzidine is still susceptible to N′-oxidation and N′-glucuronidation; therefore, the metabolic fate of mono- and diarylamines may not be that different, with the major difference being that a monoacetylated benzidine derivative can still be bound to DNA. Studies in rodents suggest that N-acetylbenzidine is an “active” metabolite (i.e., given that it can be further metabolized into reactive metabolites that can alter DNA), while N,N′-diacetylbenzidine is most likely a detoxified metabolite.15 Finally, we maintain that the revised figure does not change our conclusions that slow N-acetylation by NAT2 decreases the risk for benzidine-induced bladder cancer. As indicated in our article, these results suggest the existence of key differences in the metabolism of mono- and diarylamines, and their interaction with genotype, to affect individual susceptibility to bladder cancer. Yours sincerely, The authors wish to thank Terry Zenser for his helpful comments to this response. Tania Carreón, Fred F. Kadlubar, Avima M. Ruder, Paul A. Schulte, Richard B. Hayes, Martha Waters, Delores J. Grant, Robert Boissy, Douglas A. Bell, George P. Hemstreet III, Songnian Yin, Grace K. Lemasters, Nathaniel Rothman
Aims: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3α,17β-diol-glucuronide (AAG) levels and the prostate cancer risk. Results: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites (p=0.02), but not Blacks (p=0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15D85Y polymorphism was directly associated with the prostate cancer risk (OR=2.70, 95% CI=1.28, 5.55). Conclusions: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215D85Y with an increased prostate cancer risk.
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