Quantitative and Temporal Relationships between DNA Adduct Formation in Target and Surrogate Tissues: Implications for Biomonitoring

Nesnow, Stephen; Ross, Jeffrey A.; Nelson, Garret B.; Holden, Katrina; Erexson, Gregory L.; Kligerman, Andrew D.; Gupta, Ramesh C.

doi:10.2307/3431697

Cited by 9 publications

(5 citation statements)

References 12 publications

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“…Many human cell systems, including hepatocytes, cultured bronchus and primary lymphocytes have been shown to metabolize BP and other carcinogens, to reactive metabolites which form chromatographically identical DNA adducts to those found in animal models (35)(36)(37). Furthermore, the levels of DNA adducts found in peripheral blood lymphocytes of rats is comparable to that found in human peripheral blood lymphocytes obtained from humans after exposure to a variety of PAHs (38). However, human hepatocytes were shown to have a greater total level of carcinogen-DNA adducts when compared to rat hepatocytes exposed to the same concentration of carcinogen (36).…”

Section: Discussionsupporting

confidence: 55%

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Smith

Gupta

1996

Carcinogenesis

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There is a growing need for short-term assays which can assess the mechanisms and efficacy of cancer chemopreventive agents. In the present study we have employed a microsome-mediated test system concomitantly with DNA adduct detection to assess the efficacy of five chemopreventive agents, N-acetylcysteine, butylated hydroxytoluene (BHT), curcumin, oltipraz, and ellagic acid. 32P-Postlabeling analysis of DNA incubated with benzo[a]pyrene (BP) in the presence of Aroclor 1254-induced microsomes produced two major adducts: one derived from the interaction of benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) with deoxyguanosine (dG) and the other from further activation of 9-OH-BP (309 and 34 adducts/10(7) nucleotides, respectively). With the exception of N-acetylcysteine, all test agents significantly altered BP-DNA adduct levels: Intervention with ellagic acid and oltipraz substantially (64-94%) inhibited both BPDE-dG and 9-OH-BP adducts, while intervention with curcumin and BHT inhibited the BPDE-dG adduct (57% and 38%, respectively) and enhanced the 9-OH-BP adduct (230% and 650%, respectively). Furthermore, ellagic acid was the only test agent observed to inhibit the anti BPDE-dG adduct in the absence of microsomal enzymes, which is consistent with the known conjugation of ellagic acid with BPDE. These results suggest that oltipraz may be acting as an inhibitor of P4501A1, the isozyme involved in activation of BP to BPDE, or by conjugation of the electrophilic species by a metabolite of oltipraz. A plausible mechanism for inhibition of the BPDE-dG adduct and enhancement of the 9-OH-BP adduct by curcumin and BHT includes inhibition of epoxide hydrolase. Our results also indicate that N-acetylcysteine does not act as an electrophilic trapping agent of BP metabolites but may exert its protective effect in vivo by various other means, including modulation of detoxification enzymes and altering DNA repair processes. These data suggest that this cell-free system in conjunction with the sensitive 32P-postlabeling DNA adduct analysis may prove a viable test system for assessing the mechanisms and efficacy of chemopreventive agents.

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Section: Discussionsupporting

confidence: 55%

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Smith

Gupta

1996

Carcinogenesis

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“…We report for the first time a prospective analysis of PAH-DNA adduct levels-a marker of biologically effective exposure to PAHmeasured in histopathologically benign target tissue, and subsequent cancer risk for the same organ. Prior prospective studies of adduct levels and cancer risk have used surrogate tissues, such as white blood cells, but the correlation between adduct levels in surrogate tissues and the target organ is questionable (41)(42)(43). In this study, we find that higher levels of PAH-DNA adducts in benign prostate specimens were associated with a modest, non-significant increased risk for prostate cancer.…”

Section: Discussionmentioning

confidence: 55%

Elevated polycyclic aromatic hydrocarbon-DNA adducts in benign prostate and risk of prostate cancer in African Americans

et al. 2012

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Carcinogen-DNA adducts, a marker of DNA damage, are capable of inducing mutations in oncogenes and tumor suppressor genes, resulting in carcinogenesis. We have shown previously that polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels in prostate cancer cases vary by cellular histology and that higher adduct levels are associated with biochemical recurrence. A nested case-control study was conducted in a historical cohort of 6692 men with histopathologically benign prostate specimens. PAH-DNA adduct levels were determined by immunohistochemistry in benign prostate specimens from 536 prostate cancer case-control pairs (59% White and 41% African American). We estimated the overall and race-stratified risk of subsequent prostate cancer associated with higher adduct levels. Prostate cancer risk for men with elevated adduct levels (defined as greater than control group median) was slightly increased [odds ratio (OR) = 1.28, 95% confidence interval (CI) = 0.98-1.67, P = 0.07]. After race stratification, elevated adduct levels were significantly associated with increased risk in African American men (OR = 1.56, CI = 1.00-2.44, *P = 0.05) but not White men (OR = 1.14, CI = 0.82-1.59, P = 0.45). Elevated PAH-DNA adduct levels were significantly associated with 60% increased risk of prostate cancer among cases diagnosed 1-4 years after cohort entry (OR = 1.60, CI = 1.07-2.41) with a greater risk observed in African Americans within the first 4 years of follow-up (OR = 4.71, CI = 1.97-11.26, ***P = 0.0005). Analyses stratified by age or tumor grade revealed no additional significant heterogeneity in risk. Increased prostate cancer risk associated with high PAH-DNA adduct levels in benign prostate was found only in African Americans; risk was greatest within 4 years of follow-up, possibly reflecting a carcinogenic process not yet histologically detectable.

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“…According to a model proposed by Breverick and Gaudemack (1999), the proximal tumors were attributed to methylating carcinogens and distal tumors were attributed to bulky-adduct–forming carcinogens. Relevant to this view are the published reports that B(a)P is capable of forming bulky DNA adducts in target tissues (Nesnow et al 1993; Ramesh and Knuckles 2006). We hope to bring to light more information on the factors that underlie the differential distribution of polyps once our studies on spatial and temporal distribution of B(a)P-DNA adducts in the Apc Min mouse that received B(a)P in saturated versus unsaturated fat are completed.…”

Section: Discussionmentioning

confidence: 99%

Dietary Fat–Influenced Development of Colon Neoplasia in Apc^Min Mice Exposed to Benzo(a)pyrene

et al. 2009

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Colorectal cancer, responsible for 50,000 deaths per year, is a contributing factor for considerable mortalities in the United States. Consumption of well-done red meat and saturated fats rich in polycyclic aromatic hydrocarbons may be one of the causative factors for sporadic colon cancer. The objective of this study was to investigate whether the formation of colon tumors in adult ApcMin mice was influenced by the ingestion of different types of fat containing benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon compound. Treatment consisted of 50 and 100 μg B(a)P/kg body weight dissolved in peanut or coconut oil (representatives of unsaturated and saturated fats, respectively) administered daily to six-week-old male ApcMin mice via oral gavage for sixty days. At the end of exposure, mice were sacrificed; jejunum and colons were retrieved and preserved in 10% formalin for observation for gross pathological changes. An increased prevalence of adenomas in colons of mice that ingested B(a)P through saturated dietary fat compared to unsaturated fat and controls (p < .05) was noticed. Interestingly, we also observed adenomas with high-grade dysplasia in the B(a)P + saturated fat group, and these incidences were frequent at the 100 μg/kg B(a)P dose. On the other hand, the B(a)P-alone and unsaturated-fat groups did not show significant differences in the numbers of adenomas and invasive tumors in the both jejunum and the colon. Our studies established that dietary fat, especially saturated fat, potentiates the development of colon tumors caused by B(a)P in the ApcMin mouse.

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Quantitative and Temporal Relationships between DNA Adduct Formation in Target and Surrogate Tissues: Implications for Biomonitoring

Cited by 9 publications

References 12 publications

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Elevated polycyclic aromatic hydrocarbon-DNA adducts in benign prostate and risk of prostate cancer in African Americans

Dietary Fat–Influenced Development of Colon Neoplasia in Apc^Min Mice Exposed to Benzo(a)pyrene

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Quantitative and Temporal Relationships between DNA Adduct Formation in Target and Surrogate Tissues: Implications for Biomonitoring

Cited by 9 publications

References 12 publications

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents

Elevated polycyclic aromatic hydrocarbon-DNA adducts in benign prostate and risk of prostate cancer in African Americans

Dietary Fat–Influenced Development of Colon Neoplasia in ApcMin Mice Exposed to Benzo(a)pyrene

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Dietary Fat–Influenced Development of Colon Neoplasia in Apc^Min Mice Exposed to Benzo(a)pyrene