Biomedical subjects

Dhimant Desai

Publications and source records attributed to Dhimant Desai.

23 records · Page 2Linked to original sources

PubMed2002

Identification of tobacco-derived compounds in human pancreatic juice.

Cancer of the pancreas is the fourth leading cause of cancer mortality in the USA with an estimated 28 900 deaths in 2001. Several factors have been implicated in the etiology of this disease. However, at present, only cigarette smoking has been positively associated with pancreatic cancer. It is our working hypothesis that tobacco-derived compounds can be delivered to the pancreas where, upon metabolic activation, they can initiate carcinogenesis. Our current investigation was conducted to determine whether cotinine and tobacco-specific nitrosamines (TSNA) are present in human pancreatic juice. Smoking status was assessed by the determination of levels of urinary cotinine and was further supported by quantifying nicotine in hair. The TSNA were extracted from the pancreatic juice of 18 smokers and 9 nonsmokers by supercritical carbon dioxide that contained 10% methanol. The extracts were analyzed for TSNA, namely, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), by gas chromatography with mass spectrometric detection using a selected ion monitoring technique (GC-SIM-MS). Twenty-three extracts of human pancreatic juice were also analyzed for the presence of the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by GC-SIM-MS and by gas chromatography interfaced wit a thermal energy analyzer (GC-TEA; TEA, a nitrosamine-specific detector). Cotinine was detected in all analyzed samples of pancreatic juice from smokers (129 +/- 150 ng/mL juice; mean +/- standard deviation) and was present in only two of the nine samples of pancreatic juice from nonsmokers. Its levels in these two samples were 7 and 9 ng/mL juice. NNK was detected in 15 of 18 samples (83%) from smokers at levels from 1.37 to 604 ng/mL pancreatic juice. In nine samples of pancreatic juice from nonsmokers, NNK ranged from not detected (in three samples) to 96.8 ng/mL juice. In pancreatic juice from smokers the mean level of NNK (88.7 +/- 161 ng/mL juice) was significantly higher (p < 0.04) than in that from nonsmokers (12.4 +/- 31.7 ng/mL juice). In addition to NNK, NNN was found in two samples of pancreatic juice of smokers at levels of 68.1 and 242 ng/mL juice; NNN was not detected in any other sample. NNAL was present in 8 of 14 pancreatic juice samples (57%) from smokers and in three of nine samples (33%) from nonsmokers. This research presents preliminary data that supports the hypothesis that pancreatic tissue is exposed to TSNA and that they may be important contributors to pancreatic carcinogenesis in humans.

Carcinogens↗

PubMed2002

Synthesis, in vitro metabolism, cell transformation, mutagenicity, and DNA adduction of dibenzo[c,mno]chrysene.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants. Due to its structural similarity with the potent carcinogen dibenzo[a,l]pyrene (DB[a,l]P) and because of its environmental presence, dibenzo[c,mno]chrysene (naphtho[1,2-a]pyrene, N[1,2-a]P) is of considerable research interest. We therefore developed an efficient synthesis of N[1,2-a]P, and examined its in vitro metabolism by male Sprague Dawley rat liver S9 fraction. Its mutagenic activity in S. typhimurium TA 100 and its morphological cell transforming ability in mouse embryo fibroblasts were evaluated. On the basis of spectral analyses, the in vitro major metabolites were identified as the fjord region dihydrodiol trans-9,10-dihydroxy-9,10-dihydro-N[1,2-a]P (N[1,2-a]P-9,10-dihydrodiol), the K-region diols N[1,2-a]P-4,5-dihydrodiol and N[1,2-a]P-7,8-dihydrodiol, and also the 1-, 3-, and 10-hydroxy-N[1,2-a]P; the structure of N[1,2-a]P-9,10-dihydrodiol was also confirmed by independent synthesis. In assays with S. typhimurium TA 100, N[1,2-a]P-9,10-dihydrodiol was half as mutagenic as (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-dihydrodiol) at > or =4 nmol/plate. N[1,2-a]P-9,10-dihydrodiol was much more mutagenic than N[1,2-a]P at all dose levels, suggesting that the N[1,2-a]P-9,10-dihydrodiol is the likely proximate mutagen of N[1,2-a]P. Evaluation of morphological cell transformation in C3H10T1/2C18 mouse embryo fibroblasts revealed that N[1,2-a]P was comparable to B[a]P. We further examined the pattern of in vitro adduct formation between calf thymus DNA and (+/-)-anti-9,10-dihydroxy-9,10-dihydro-11,12-epoxy-9,10,11,12-tetrahydro-N[1,2-a]P (N[1,2-a]PDE) and found that dG-adduct formation is 2.9-fold greater than dA-adduct formation. On the basis of our results and those reported in the literature, our working hypothesis is that N[1,2-a]P may be added to the list of potent carcinogens that includes DB[a,l]P. This hypothesis is currently being tested in our laboratory.

Animals↗

PubMed2002

Comparative tumorigenicity of the environmental pollutant 6-nitrochrysene and its metabolites in the rat mammary gland.

Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalation and/or ingestion. Therefore, one of the goals of this study was to determine the propensity of the environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer following its oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an established mammary carcinogen in the same animal model, was used as a positive control and trioctanoin as a negative control. Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with 6-NC at 50, 25, or 12.5 micromol/rat or PhIP at 50 micromol/rat in 500 microL of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats were decapitated, necropsied, and evaluated histologically. The most common mammary tumors were adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean +/- standard deviation) of mammary adenocarcinomas induced by these two carcinogens at the highest dose (6-NC: 90%, 3.73 +/- 2.74; PhIP: 83%, 2.62 +/- 2.58) were significantly higher than those in control rats (10%, 0.10 +/- 0.31). However, there were no statistically significant differences between groups treated with 6-NC and PhIP or among groups receiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bind covalently to DNA; however, it remains to be determined whether it can also induce DNA base oxidation. Thus, employing the same route of administration, our studies revealed no effect of 6-NC on the basal level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the mammary gland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesis assay in the normal, noninvolved tissue and in mammary tumors. This result suggests that covalent DNA binding of 6-NC metabolites is important in the induction of mammary cancer in rats. Therefore, the other goal of this study was to compare the tumorigenic activities of 6-NC and its metabolites in the rat mammary gland by intramammary administration. This route has also been used in our laboratory to induce mammary cancer in the rat by 6-NC and is employed here to avoid systemic effects and to determine the role of the mammary gland in the metabolic activation of 6-NC and its metabolites. Toward this end, a new method was developed to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2-DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of the results, the carcinogenic potency toward the mammary gland is ranked in the following order: 6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested, 1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its reduced product 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly different from 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively, these results suggest that metabolites derived from both ring-oxidation and nitroreduction contribute to the overall carcinogenicity of 6-NC in the rat mammary gland.

8-Hydroxy-2'-Deoxyguanosine↗

PubMedDate not supplied

Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, suppresses the growth of carcinogen-induced mammary tumors.

Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been shown to inhibit the development of N-methylnitrosourea (NMU)-induced rat mammary tumors when fed in the diet continuously for the duration of the carcinogenic process. The present study was designed to determine whether the inhibitory effects of SAHA occur during the initiation process or at subsequent stages in the carcinogenic process. In addition, animals with established NMU tumors were administered SAHA to determine whether SAHA could inhibit the continued growth of established mammary tumors. It was found that SAHA fed at 900 ppm in the diet inhibited tumor yields when administered from 14 days prior to NMU administration to termination (-14 to +130) and from +14 and +28 days to termination. However, SAHA had no effect on tumor yields when administered from -14 to +14 or from -14 to +50 days and then returned to the control diets for the remainder of the experimental period (130 days). These results indicate that the inhibitory effects of SAHA are not exerted at the initiation phase of NMU-induced mammary tumorigenesis and appear, instead, to inhibit the subsequent stages in tumor development. Of most interest was the ability of SAHA to inhibit the growth of established mammary tumors. Administration of SAHA in the diet at 900 ppm resulted in significant inhibition of established tumor growth. Thirty-two percent of SAHA-treated tumors exhibited partial regression compared to 12% of controls, growth was stabilized in 24% of treated tumors compared to 12% of controls while 11% exhibited complete regression compared to 0% of controls. Collectively, SAHA-treated tumors exhibited a 7-fold reduction in growth compared to untreated tumors over the test period. The results of this animal model study indicate that SAHA, when fed in the diet, serves as both a chemopreventive and chemotherapeutic agent in the absence of any detectable side effects.

Animals↗

PubMedDate not supplied

Chemopreventive efficacy of suberoylanilide hydroxamic acid (SAHA) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice.

Histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), represent a promising new class of chemopreventive agents. We have synthesized SAHA by an improved method and examined its efficacy as a dietary supplement at 450 ppm against lung tumor development in female A/J mice induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We observed significant inhibition (80%, p < 0.0001) of lung tumor multiplicity in mice treated with NNK plus SAHA compared to NNK-treated controls. SAHA inhibited the carbonyl reductive pathways of NNK in a dose-dependent manner in liver, but not lung microsomes, obtained from A/J mice. However, a significant inhibition of the a-hydroxylation pathway of NNK was observed in both lung and liver microsomes, suggesting that SAHA may act to inhibit the activation pathways of NNK metabolism. The results of this model study indicate that SAHA holds promise as a potential chemopreventive agent against lung cancer.

Animals↗