Alteration of benzo(a)pyrene biotransformation by resveratrol in ApcMin/+ mouse model of colon carcinogenesis.

Epidemiological surveys have revealed that environmental and dietary factors contribute to most of the human cancers. Our earlier studies have shown that resveratrol (RVT), a phytochemical reduced the tumor number, size and incidence of dysplasias induced by benzo(a)pyrene (BaP), an environmental toxicant in the ApcMin/+ mouse model of colon cancer. In this study we investigated to ascertain whether the preventive effects of RVT on BaP-induced colon carcinogenesis is a result of altered BaP biotransformation by RVT. For the first group of mice, 100 µg BaP/kg bw was administered in peanut oil via oral gavage over a 60 day period. For the second group, 45 µg RVT/kg bw was co-administered with BaP. For the third group, RVT was administered for 1 week prior to BaP exposure. Blood, colon and liver were collected from control and BaP/RVT-treated mice at 60 days post-BaP & RVT exposure. We have assayed activities and expression (protein & mRNA) of drug metabolizing enzymes such as cytochrome P4501A1 (CYP1A1), CYP1B1, and glutathione-S-transferase (GST) in colon and liver samples from the treatment groups mentioned above. An increased expression of CYP1A1 in liver and colon and of CYP1B1 in liver of BaP-treated mice was seen, while RVT inhibited the extent of biotransformation mediated by these enzymes in the respective tissue samples. In the case of GST, an increased expression in colon of BaP alone-treated mice was noted when RVT was administered prior to BaP or simultaneously with BaP. However, there is no change in liver GST expression between BaP and RVT treatment groups. The concentrations of BaP aqueous (phase II) metabolites were found to be greater than the organic (phase I) metabolites, suggesting that RVT slows down the phase I metabolism (metabolic activation) of BaP, while enhancing phase II metabolism (detoxification). Additionally, the BaP-DNA adduct concentrations measured in colon and liver of BaP + RVT-treated mice were low relative to their BaP counterparts. Taken together, our findings strongly suggest that RVT alleviates BaP-induced colon carcinogenesis by impairing biotransformation pathways and DNA adduct formation, and therefore holds promise as a chemopreventive agent.

Bioaccessibility of polycyclic aromatic hydrocarbons: relevance to toxicity and carcinogenesis.

INTRODUCTION: Bioaccessibility is a growing area of research in the field of risk assessment. As polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, they are the toxicants of focus to establish cancer risks in humans. Orally ingested PAHs also cause toxicity and even affect the pharmacokinetic behavior of some therapeutic agents. Toward this end, bioaccessibility is being used as a tool to assess the risk of PAHs via dietary exposures. AREAS COVERED: This review covers some in vitro bioaccessibility models for PAHs that have been used for the past one-and-a-half decade. This review also considers the factors that influence bioaccessibility and debates the merits and limitations of using a bioaccessibility concept for estimating risk from ingestion of PAH-contaminated soil and food. Finally, the authors discuss the implications of bioaccessibility for PAH-induced toxicity and cancers in the context of risk assessment. EXPERT OPINION: So far, much of the focus on PAH bioaccessibility is centered on soil as a preferential matrix. However, ingestion of PAHs through diet far exceeds the amount accidentally ingested through soil. Therefore, bioaccessibility could be exploited as a tool to assess the relative risk of various dietary ingredients tainted with PAHs. While bioaccessibility is a promising approach for assessing PAH risk arising from various types of contaminated soils, none of the models proposed appears to be valid. Bioaccessibility values, derived from in vitro studies, still require validation from in vivo studies.

Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol.

Human dietary exposure to benzo(a)pyrene (BaP) has generated interest with regard to the association of BaP with gastrointestinal carcinogenesis. Since colon cancer ranks third among cancer-related mortalities, it is necessary to evaluate the effect of phytochemicals on colon cancer initiation and progression. In this study, we investigated the preventive effects of resveratrol (RVT) on BaP-induced colon carcinogenesis in Apc(Min) mouse model. For the first group of mice, 100 µg BaP/kg body weight was administered to mice in peanut oil via oral gavage over a 60-day period. For the second group, RVT was coadministered with BaP at a dose of 45 µg/kg. For the third group, RVT was administered for 1 week prior to BaP exposure for 60 days. Jejunum, colon and liver were collected at 60 days post BaP and RVT exposure; adenomas in jejunum and colon were counted and subjected to histopathology. RVT reduced the number of colon adenomas in BaP+RVT-treated mice significantly compared to that in mice that received BaP alone. While dysplasia of varying degrees was noted in colon of BaP-treated mice, the dysplasias were of limited occurrence in RVT-treated mice. To ascertain whether the tumor inhibition is a result of altered BaP-induced toxicity of tumor cells, growth, apoptosis and proliferation of adenocarcinoma cells were assessed posttreatment with RVT and BaP. Cotreatment with RVT increased apoptosis and decreased cell proliferation to a greater extent than with BaP alone. Overall, our observations reveal that RVT inhibits colon tumorigenesis when given together with BaP and holds promise as a therapeutic agent.

Polycyclic aromatic hydrocarbons and digestive tract cancers: a perspective.

Cancers of the colon are most common in the Western world. In majority of these cases, there is no familial history and sporadic gene damage seems to play an important role in the development of tumors in the colon. Studies have shown that environmental factors, especially diet, play an important role in susceptibility to gastrointestinal (GI) tract cancers. Consequently, environmental chemicals that contaminate food or diet during preparation become important in the development of GI cancers. Polycyclic aromatic hydrocarbons (PAHs) are one such family of ubiquitous environmental toxicants. These pollutants enter the human body through consumption of contaminated food, drinking water, inhalation of cigarette smoke, automobile exhausts, and contaminated air from occupational settings. Among these pathways, dietary intake of PAHs constitutes a major source of exposure in humans. Although many reviews and books on PAHs and their ability to cause toxicity and breast or lung cancer have been published, aspects on contribution of diet, smoking and other factors toward development of digestive tract cancers, and strategies to assess risk from exposure to PAHs have received much less attention. This review, therefore, focuses on dietary intake of PAHs in humans, animal models, and cell cultures used for GI cancer studies along with epidemiological findings. Bioavailability and biotransformation processes, which influence the disposition of PAHs in body and the underlying causative mechanisms of GI cancers, are also discussed. The existing data gaps and scope for future studies is also emphasized. This information is expected to stimulate research on mechanisms of sporadic GI cancers caused by exposure to environmental carcinogens.

Effect of benzo(a)pyrene exposure on fluoranthene metabolism by mouse adipose tissue microsomes.

The present study has been undertaken to examine whether exposure to benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH) compound, influences the metabolism of fluoranthene (FLA), another PAH compound. Microsomes were isolated from the adipose tissue of mice that received 50 microg/kg BaP and incubated with FLA (3 microM) alone; FLA in combination with BaP at equimolar concentrations, and a control group that received nothing. Post-incubation, samples were extracted with ethyl acetate and analyzed for FLA metabolites by reverse-phase HPLC with fluorescence detection. The rate of FLA metabolism (pmol of metabolite/min/mg protein) was increased when microsomes from BaP-treated mice were exposed to FLA alone and FLA in combination with BaP, compared to controls. On the other hand, the difference in FLA metabolic rate between microsomes that were exposed to FLA + BaP was higher than the ones that received FLA. The microsomes from BaP-pre-treated mice produced a considerably higher proportion of FLA 2, 3-diol, and 2, 3 D FLA when microsomes were incubated with FLA. There were no differences in the FLA metabolite types formed when BaP-pre-treated mice were co-incubated with BaP and FLA than with FLA alone. The enhanced biotransformation of FLA as a result of prior and concomitant exposure to BaP may have implications for assessment of risks arising from human exposure to PAH mixtures.

Comparative metabolism of benzo(a)pyrene by ovarian microsomes of various species.

Knowledge of the ability of the female reproductive system to metabolize polycyclic aromatic hydrocarbons (PAHs) is critical to the diagnosis and management of female infertility and for risk assessment purposes. The PAHs are a family of widespread pollutants that are released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, PAHs become activated to reactive metabolites that interfere with target organ function and as a consequence cause toxicity. The extent of susceptibility to PAH exposure may depend on the ability of animals to metabolize these chemicals. The present study has been undertaken to assess whether any differences exist among mammals in the metabolism of benzo(a)pyrene (BaP), a prototypical PAH compound. Microsomes isolated from the liver and ovaries of rats, mice, goats, sheep, pigs, and cows were incubated with 5 microM BaP. Postincubation, samples were extracted with ethyl acetate and analyzed for BaP/metabolites by reverse-phase HPLC with fluorescence detection. The rate of metabolism (pmol of metabolite/min/mg protein) was found to be more in liver than in ovary in all the species studied (P < 0.05). The differences in metabolite concentrations were statistically significant (P < 0.0001) among the various species in both organs studied. Multiple species comparison also revealed that the differences were statistically significant (P < 0.001) between rodents (rat and mouse) and higher mammals (ewe, sow, and cow). Even among the higher mammals, in a majority of the cases, the differences in metabolite concentrations were significantly different (P < 0.001) both in ovary and liver. The BaP metabolites identified were 4,5-diol; 7,8-diol; 9,10-diol; 3-hydroxy BaP; and 9-hydroxy BaP. The rodent microsomes produced considerably higher proportion of BaP 4,5-diol and 9,10-diol than did cow, sow, goat, and sheep. However, microsomes from higher mammals converted a greater proportion of BaP to 3-hydroxy and 9-hydroxy BaP, the detoxification products of BaP. Overall, our results revealed a great variation among species to metabolize BaP.