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Biomedical subjects

A Rivenson

Publications and source records attributed to A Rivenson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate.

Phenethyl isothiocyanate (PEITC), which occurs in certain cruciferous vegetables, was tested for its ability to inhibit lung tumorigenesis in rats induced by the tobacco-specific nitrosamine 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in a study involving virtually lifelong administration of both compounds. In addition, two biomarkers of NNK metabolism [4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts and 4-(methylnitrosamino-1-3-pyridyl-1-butanol and its glucuronide in urine] were quantified in randomly selected rats during the course of the study. The rats were assigned to groups as follows: NNK, 2 ppm in drinking water, 60 rats; NNK, 2 ppm in drinking water and PEITC, 3 micromol/g NIH-07 diet, 60 rats; PEITC, 3 micromol/g NIH-07 diet, 20 rats; and untreated controls, 20 rats. NNK was added to the drinking water for 111 weeks and PEITC to the diet for 1 prior to NNK administration and then throughout the 111-week course of treatment. There were no significant differences in body weights or survival among the groups. There were no significant effects of PEITC on blood chemistry or hematology. NNK induced lung tumors (adenoma and/or adenocarcinoma) in 70% of the rats. In the group treated with NNK plus PEITC, 5% of the rats had lung tumors, which was not different from that of control rats. PEITC also appeared to inhibit progression of benign to malignant pancreatic tumors. At intervals during the study, blood was withdrawn from selected rats, and 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts, which are formed upon metabolic activation of NNK, were quantified. The hemoglobin adducts were significantly repressed throughout the study in the rats treated with NNK plus PEITC compared to those treated with NNK. The 24-h urine sample of several rats was analyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronide. A 4-6-fold increase in the sum of these metabolites was observed in the rats treated with NNK plus PEITC compared to those treated with NNK. This is also consistent with inhibition of metabolic activation of NNK by PEITC. Collectively, the results of this study provide strong evidence for the efficacy of PEITC as a chemopreventive agent against NNK-induced pulmonary carcinogenesis in rats and indicate that two biomarkers of NNK metabolism, measurable in tobacco consumers, can be modulated in a predictable way by PEITC administration.

Animals↗
PubMed1995

Enhancement of experimental colon carcinogenesis by dietary 6-phenylhexyl isothiocyanate.

Naturally occurring and related synthetic isothiocyanates are known to exert chemopreventive effects in several organs in rodent models. The present study was designed to investigate the efficacy of 6-phenylhexyl isothiocyanate (PHITC), a potent chemopreventive agent in the lung tumor model in strain A mice, on azoxymethane-induced colon tumorigenesis. Another aim was to study the modulating effect of PHITC on colonic mucosal and tumor phospholipase A2 (PLA2), phosphatidylinositol-specific phospholipase C (PI-PLC), lipoxygenase (LOX), and cyclooxygenase (COX) activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 320 or 640 ppm of PHITC representing 40 and 80% maximum tolerated dose levels, respectively. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All animals continued on their respective dietary regimen for 52 weeks after the carcinogen treatment; then the study was terminated. Colonic mucosa and tumors were analyzed for PLA2, PI-PLC, prostaglandin (PG) E2, COX, and LOX activities. Intestinal tumors were evaluated histopathologically and classified as invasive or noninvasive adenocarcinomas. Intestinal tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal; tumors/tumor-bearing animal) were compared among the dietary groups. At the 640-ppm dose level, dietary PHITC significantly increased the incidence of intestinal (small intestine plus colon) adenocarcinomas (P < 0.05) as well as the multiplicities of invasive and noninvasive adenocarcinomas of the colon (P < 0.05 to 0.01). At the 320-ppm dose level, PHITC increased the multiplicity (tumors/animal) of noninvasive adenocarcinomas and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05). Dietary PHITC also increased the colon tumor volume (2- to 4.3-fold) in a dose-dependent manner. Moreover, PHITC significantly enhanced the activities of PLA2 (50-100%) and levels of PGE2 (2-fold) in the colonic mucosa and in tumors, but it had no significant effect (P > 0.05) on PI-PLC activity. The formation of COX metabolites, particularly PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2, as well as LOX metabolites such as 8(S)-, 12(S)- and 15 (S)-hydroxyeicosatetraenoic acids, were significantly increased in the colonic mucosa and tumors of animals that were fed 640 ppm of PHITC. Although the exact mechanism by which PHITC promotes colon tumorigenesis remains to be elucidated, it is likely that the tumor-promoting effects of PHITC may, at least in part, be related to increased eicosanoid metabolism in the colon.

Animals↗
PubMed1995

Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate.

Previous studies from this laboratory have established that caffeic acid esters present in propolis, a natural resin produced by honey bees, are potent inhibitors of human colon adenocarcinoma cell growth, carcinogen-induced biochemical changes, and preneoplastic lesions in the rat colon. The present study was designed to investigate the chemopreventive action of dietary phenylethyl-3-methylcaffeate (PEMC) on azoxymethane-induced colon carcinogenesis and to examine the modulating effect of PEMC on phosphatidylinositol-specific phospholipase C (PI-PLC), phospholipase A2, lipoxygenase (LOX), and cyclooxygenase activities in the colonic mucosa and tumor tissues in male F344 rats. At 5 weeks of age, groups of rats were fed the control (modified AIN-76A) diet, or a diet containing 750 ppm of PEMC. At 7 weeks of age, all animals except those in the vehicle (normal saline)-treated groups were given 2 weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All groups were maintained on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Both colonic mucosa and tumors were analyzed for PI-PLC, phospholipase A2, cyclooxygenase, and LOX activities. The results indicate that dietary administration of PEMC significantly inhibited the incidence and multiplicity of invasive, noninvasive, and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05-0.004). Dietary PEMC also suppressed the colon tumor volume by 43% compared to the control diet. Animals fed the PEMC diet showed significantly decreased activities of colonic mucosal and tumor PI-PLC (about 50%), but PEMC diet had no effect on phospholipase A2. The production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the LOX pathway from arachidonic acid was reduced in colonic mucosa and tumors (30-60%) of animals fed the PEMC diet as compared to control diet. PEMC had no effect on the formation of colonic mucosal cyclooxygenase metabolites but inhibited the formation in colonic tumors by 15-30%. The precise mechanism by which PEMC inhibits colon tumorigenesis remains to be elucidated. It is likely that the chemopreventive action may be related, at least in part, to the modulation of PI-PLC-dependent signal transduction and LOX-mediated arachidonic acid metabolism.

Animals↗
PubMed1995

Secondary nitroalkanes: induction of DNA repair in rat hepatocytes, activation by aryl sulfotransferase and hepatocarcinogenicity of 2-nitrobutane and 3-nitropentane in male F344 rats.

The secondary nitroalkanes, 2-nitropropane, 2-nitrobutane, 3-nitropentane, 2-nitroheptane, nitrocyclopentane and nitrocyclohexane, as well as the primary nitroalkanes, 1-nitropropane, 1-nitrobutane, 1-nitropentane and 1-nitroheptane, were examined for their ability to induce DNA repair in rat hepatocytes and to serve as substrates for activation by partially purified rat liver aryl sulfotransferase in vitro. All of the secondary, but none of the primary nitroalkanes examined, induced significant DNA repair in rat hepatocytes. Also, the nitronates of all of the secondary nitroalkanes, but none of the primary nitroalkanes, served as substrates for the aryl sulfotransferase-catalysed production of 8-aminoguanosine and 8-oxoguanosine from guanosine in vitro. In a carcinogenicity assay using male F344 rats, the secondary nitroalkanes, 2-nitrobutane and 3-nitropentane, produced a highly significant incidence of hepatocarcinoma with metastases to the lungs, whereas the primary nitroalkane, 1-nitrobutane, was not carcinogenic. While a low incidence of hepatocarcinoma was also produced by cyclopentanone oxime, the results were not statistically significant. Since the secondary nitroalkane, 2-nitropropane, in contrast to the primary nitroalkane, 1-nitropropane, was also previously shown to be hepatocarcinogenic in rats, it is probable that secondary nitroalkanes constitute a hitherto unrecognized class of chemical carcinogens.

Animals↗
PubMed1995

Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent.

Epidemiological and laboratory animal model studies have suggested that nonsteroidal anti-inflammatory drugs reduce the risk of development of colon cancer. The present study was designed to investigate the chemopreventive action of 160 and 320 ppm (equivalent to 40 and 80% maximum tolerated doses) sulindac, a nonsteroidal anti-inflammatory drug, fed during initiation and postinitiation stages and 320 ppm sulindac fed during promotion/progression stages of azoxymethane-induced colon carcinogenesis in male F344 rats. Also investigated was the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phosphatidylinositol-specific phospholipase C, lipoxygenase, and cyclooxygenase activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 160 and 320 ppm of sulindac. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. Animals intended for tumor promotion/progression study were administered 320 ppm of sulindac in diet starting at 14 weeks after a second azoxymethane treatment. All animals continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phosphatidylinositol-specific phospholipase C, prostaglandin E2, cyclooxygenase, and lipoxygenase activities. The levels of sulindac and its metabolites in stomach, cecal, and fecal contents and in serum were analyzed. The results indicate that dietary sulindac at 160 and 320 ppm levels inhibited the incidence of invasive and noninvasive adenocarcinomas of the colon (P < 0.01-0.001) as well as their multiplicity (P < 0.01-0.0001) in a dose-dependent manner. Also, feeding sulindac during promotion/progression stages significantly suppressed the incidence (P < 0.0001) and multiplicity (P < 0.0001) of colonic adenocarcinomas. Dietary sulindac also suppressed the colon tumor volume by > 52-62% compared to the control diet. Dietary sulindac significantly decreased the activities of phosphatidylinositol-specific phospholipase C (32-51%) and levels of prostaglandin E2 (> 40%) in the colonic mucosa and tumors, but it had no significant (P > 0.05) effect on phospholipase A2 activity. The formation of cyclooxygenase metabolites, particularly prostaglandin E2, prostaglandin F2 alpha, prostaglandin D2, 6-ketoprostaglandin F1 alpha, and thromboxane B2, and lipoxygenase metabolites such as 8(S)- and 12(S)-hydroxyeicosatetraenoic acids were significantly reduced in colonic mucosa and tumors of animals fed 320 ppm sulindac.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1995

Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound.

Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.

Animals↗
PubMed1995

Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats.

Agents that are ubiquitous in the environment and are known inducers of mammary cancer in rodents can be regarded as potential causes of human cancer and need to be evaluated more completely. Therefore, the purpose of this study was to determine under identical conditions the relative carcinogenic potency in the mammary glands of rats of benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with B[a]P, 1-NP or PhIP. Each compound was given at 50 mumol/rat/week in 0.5 ml trioctanoin for a total dose of 400 mumol/rat. Forty-one weeks after the last carcinogen administration, rats were killed. In the 1-NP-treated rats, treatment elicited primarily benign tumors. In contrast, the B[a]P- and PhIP-treated rats developed both malignant and benign tumors. The incidence of adenocarcinomas in rats treated with B[a]P or PhIP was comparable and significantly higher than that in animals receiving trioctanoin only. The incidence of benign tumors (fibroadenomas, desmoplastic adenomas and adenomas) observed in animals treated with B[a]P or 1-NP was comparable and significantly higher than that in animals given PhIP or trioctanoin. This is the first report describing the carcinogenic activity of PhIP, given by gavage, in the mammary gland of CD rats and ranking the carcinogenic potency observed under identical conditions, of three agents (B[a]P congruent to PhIP > 1-NP) that are prevalent in the human environment.

Animals↗
PubMed1995

Mammary carcinogenicity in female CD rats of a diol epoxide metabolite of fluoranthene, a commonly occurring environmental pollutant.

We examined the mammary carcinogenicity in CD rats of anti-2,3-dihydroxy-1,10b-epoxy-10b,1,2,3-tetrahydro-fluoranthene (FDE), a genotoxic metabolite of the environmental pollutant fluoranthene. FDE (2 mumol or 10 mumol) in 0.1 ml dimethyl sulfoxide (DMSO) was injected beneath each of the three left thoracic nipples of groups of 20 rats each, with 0.1 ml DMSO alone being injected under the right nipples. On the next day, the procedure was repeated for the three inguinal nipples on each side. anti-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene (BcPDE, 2 mumol per nipple) was used as a positive control and DMSO alone as a negative control. Tumor development was assessed weekly by palpation and the experiment was terminated after 41 weeks. Eighty five percent of the rats in each of the FDE treated groups developed histologically confirmed mammary tumors, compared to 11% in the DMSO treated animals (P < 0.01). Most tumors were on the left side. The lower dose of FDE induced a significant number of adenomas while the higher dose induced significant incidences of both adenomas and adenocarcinomas compared to controls. BcPDE was a powerful mammary carcinogen, confirming our previous observation. The results of this study demonstrate the carcinogenicity of FDE to the CD rat mammary gland. Since FDE is a potentially transportable human metabolite of fluoranthene, its possible role as an etiologic factor in breast cancer deserves further study.

Animals↗
PubMed1995

Mammary carcinogenicity in female CD rats of fjord region diol epoxides of benzo[c]phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene.

We compared the mammary carcinogenicity in female CD rats of three fjord region diol epoxides to test our hypothesis that such sterically hindered molecules would be potent carcinogens. The diol epoxides tested were racemic anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene (BcPDE), anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrobenzo[g]chrysene (BgCDE) and anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l ]pyrene (DB[a,l]PDE). Each diol epoxide was dissolved in dimethylsulfoxide (DMSO) and injected under the six nipples on the left side of the rat, with DMSO only being injected under the nipples on the right side. The total dose of each diol epoxide was 1.2 mumol/rat and there were 20 rats/group. The experiment was terminated 41 weeks after treatment. All three diol epoxides were potent mammary carcinogens, with activity greater than previously observed for a bay region diol epoxide, anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). DB[a,l]PDE induced tumors most rapidly, followed by BcPDE and BgCDE. However, different types of tumors were induced. For induction of adenomas and adenocarcinomas, BcPDE and BgCDE had comparable potency; both were more active than DB[a,l]PDE. In contrast, for induction of sarcomas, DB[a,l]PDE was significantly more active than BcPDE and BgCDE. The results of this study support our hypothesis that sterically hindered fjord region diol epoxides are potent mammary carcinogens in the rat.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1995

Dietary modulation of the carcinogenicity of the heterocyclic amines.

UNLABELLED: Heterocyclic amines (HCAs) are potent mutagens and carcinogens formed during cooking of meats or fish. They are, therefore, widely consumed by humans. PURPOSE: A series of studies explore modulation of the mutagenicity and carcinogenicity of typical HCAs like 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP), through dietary fat, green or black tea, and tea polyphenols like epigallocatechin gallate (EGCG) and theaflavin gallate (TFG). Also examined was the carcinogenicity of the bacterial metabolite of IQ, 7-oxo-IQ. METHODS: Male and female F344 rats were fed diets with 75 ppm IQ for 12 months, and containing 5% or 20% corn oil. Complete necropsies after 15 months (males), or 18 months (females) were performed. Modification of the action of IQ and of PhIP in tests for bacterial mutagenicity (Ames test) or DNA repair in male rat hepatocytes (Williams test) by teas, EGCG or TFG was studied. Also compared was the activity of IQ and of 7-oxo-IQ in the tests of Ames and of Williams, and their carcinogenicity in male F344 rats upon intrarectal infusion. RESULTS: A high fat diet increased the carcinogenicity of low levels of IQ at several target organs. Multiple benign and malignant sebaceous skin tumors were noted in males but not in females. Green or black teas, EGCG, and TFG sharply reduced the mutagenicity of IQ and PhIP, and especially lowered the activity of IQ and of PhIP in the Williams test. 7-Oxo-IQ was active only in the Ames test, but not in the Williams test. Also, it was not carcinogenic, confirming that chemicals positive in the Ames test but negative in the Williams test are not likely carcinogens. CONCLUSIONS: The in vitro and in vivo effects of HCAs can be modified by dietary components such as fats or teas. An understanding of the underlying mechanisms may provide practical and realistic means of risk assessment, and may lower the risk associated with these nutritional carcinogens widespread in the human environment.

Amines↗
PubMed1994

Evidence supporting the role of DNA pyridyloxobutylation in rat nasal carcinogenesis by tobacco-specific nitrosamines.

The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) both induce nasal tumors in rats and have a common metabolic activation pathway leading to pyridyloxobutylation of DNA. The role of DNA pyridyloxobutylation in rat nasal carcinogenesis has not been evaluated previously. In this study, we used gas chromatography-mass spectrometry to compare levels of 4-hydroxyl-1-(3-pyridyl)-1-butanone-releasing adducts formed by pyridyloxobutylation of rat nasal mucosa DNA after treatment with either NNK, NNN, or deuterated analogues of NNK. The latter were [4,4-D2]NNK, a stronger nasal cavity carcinogen than NNK, and [CD3]NNK, which has carcinogenic activity equivalent to NNK. We also investigated toxicity to the nasal mucosa and levels of O6-methylguanine in the DNA of this tissue in rats treated with NNK and its deuterated analogues. Rats were given three times weekly s.c. injections of the respective nitrosamines for 4 weeks and then sacrificed 24 h after the final injection. The nasal mucosa was separated into the olfactory and respiratory portions. In the rats treated with [4,4-D2]NNK, levels of O6-methylguanine in DNA from both the olfactory and respiratory portions of the nasal mucosa were significantly lower and levels of 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts higher than in the rats treated with equivalent doses of the less carcinogenic compounds NNK or [CD3]NNK. 4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing adducts were also detected in the nasal mucosa DNA of the rats treated with NNN. In the comparative study of NNK and its deuterated analogues, the histology of the nasal mucosa did not appear to be markedly different among these groups. Collectively, the results of this study provide strong evidence that DNA pyridyloxobutylation is important in rat nasal cavity carcinogenesis by NNK and NNN.

Alkylation↗
PubMed1994

Genotoxicity and carcinogenicity in rats and mice of 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7- one: an intestinal bacterial metabolite of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline.

BACKGROUND: Compounds formed on the surface of fried or grilled meat and fish may be associated with increased risk of colon cancer. Normal intestinal bacteria can convert one of these compounds, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), to the 7-hydroxy metabolite, 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7-o ne (7-OHIQ), a direct-acting mutagen. PURPOSE: We studied the genotoxicity and carcinogenicity of 7-OHIQ to determine if it is responsible for the colon-specific activity of IQ. METHODS: The effects of pure, synthetic 7-OHIQ on DNA were evaluated in the Ames Salmonella typhimurium TA98 test, with and without an induced rat liver S9 fraction, and in the Williams DNA repair test using freshly explanted rat hepatocytes. 7-OHIQ was also subjected to an in vivo bioassay for 21 months by long-term intrarectal infusion in male F344 rats, using IQ and N-nitrosomethylurea (NMU) given intrarectally as positive tumor-producing controls. The standard NIH-07 rodent diet was supplemented with 15% corn oil to maximize any effect of the infused materials on the colon. A parallel bioassay involved intraperitoneal injection of 7-OHIQ in newborn mice, followed by dietary administration from week 11 to week 67. Again, IQ and NMU were used as positive controls. RESULTS: We confirmed that 7-OHIQ is a direct-acting mutagen in the Ames test, with added S9 liver fraction giving higher mutagenicity. 7-OHIQ was negative in the Williams test, whereas IQ was positive. 7-OHIQ did not induce colon cancer in rats, and in the newborn mouse test it produced only a low incidence of liver neoplasms. CONCLUSIONS: 7-OHIQ is not genotoxic, for to be so classified it must be definitely positive in both the Ames and Williams tests; moreover, it is not carcinogenic, in marked contrast to IQ and NMU.

Animals↗
PubMed1994

Potent mammary carcinogenicity in female CD rats of a fjord region diol-epoxide of benzo[c]phenanthrene compared to a bay region diol-epoxide of benzo[a]pyrene.

Two diol-epoxide metabolites of benzo[c]phenanthrene and benzo[a]pyrene, polynuclear aromatic hydrocarbons which occur in the environment, were tested for carcinogenicity by direct injection into the mammary fat pads of female CD rats. The compounds anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene (BcPDE), a fjord region diol-epoxide, and anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, a bay region diol-epoxide, were applied at total doses of 12.2 mumol. 6-Nitrochrysene was applied at the same dose as a positive control (K. El-Bayoumy, A. Rivenson, P. Upadhyaya, Y-H. Chae, and S. S. Hecht, Cancer Res. 53: 3719-3722, 1993). The sterically hindered fjord region diol-epoxide BcPDE was a powerful mammary tumorigen and carcinogen, rapidly inducing significantly more fibroadenoma and adenocarcinoma than either of the other compounds. Anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene was a weaker mammary tumorigen than BcPDE and 6-nitrochrysene. The results of this study provide the first evidence for mammary tumorigenicity of polynuclear aromatic hydrocarbon diol-epoxides and demonstrate the potent mammary carcinogenicity of BcPDE.

Adenocarcinoma↗
PubMed1994

The role of fat and calcium in the production of foci of aberrant crypts in the colon of rats fed 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine.

The modulation by dietary fat levels of intestine carcinogenesis is well documented. New developments suggest that calcium ions may also play a role. A rapid bioassay, the induction of foci of aberrant crypts in the colon, was used to explore the interaction between dietary fat and calcium. Male F344 rats 6 weeks of age were placed on diets containing 5 or 20% corn oil, and 0.04 or 0.32% calcium ion, as calcium lactate. Each dietary group was fed 400 ppm 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), and negative controls received the diets alone. A positive control group was given 2 mg N-nitrosomethylurea (NMU) intrarectally four times in a 2-week period. All rats were killed after 9 weeks. The intestinal tract was rinsed with Krebs-Ringer buffer. After staining a 6-cm segment of the descending colon and rectum with 0.2% methylene blue, foci of aberrant crypts were evaluated microscopically. With PhlP as a carcinogen, the rats on a high-fat, low-calcium level had more foci of aberrant crypts than animals on a low-fat level. With the higher calcium level, there were fewer foci and aberrant crypts, but the effect of fat was still significant. With NMU and a low-calcium level, the effect of fat level was evident. However, with the higher calcium intake, there were considerably more foci of aberrant crypts than on the low-calcium level, and the effect of the dietary fat level was not obvious.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Role of fat and calcium in cancer causation by food mutagens, heterocyclic amines.

We investigated the modulation by dietary corn oil and calcium levels of carcinogenesis by heterocyclic amines (HCA), a new class of important carcinogens in the human nutritional environment, since they are formed during cooking. Two approaches involved (i) a chronic bioassay in male and female F344 rats, and (ii) an abbreviated test, the induction of foci of aberrant crypts in the colon in male F344 rats. One typical HCA, 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) was fed at 75 ppm for 12 months to male and female rats that were held three and six months longer, respectively, on control diets. Neoplasms were induced in the Zymbal gland, skin (predominantly in male rats), liver, mammary and preputial glands, colon, and lung. Diets with 23.5% corn oil increased carcinomas in the liver in males, and in the mammary gland in females, compared with a 5% corn oil diet. Males on the low-fat diet had more cancers in the lip, and females had more ear duct cancers, than did rats on the high-fat diet. Another HCA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), fed at 400 ppm for nine weeks induced foci of aberrant crypts in the lower intestinal tract of male F344 rats. There were significantly more aberrant crypts on the high-fat than on the low-fat diet. On the low-fat diet, there were fewer aberrant crypts on the higher calcium level. Thus, dietary fat modulates the carcinogenic action of HCA food carcinogens in specific organs of male and female F344 rats. Also, both fat and calcium affected the induction of aberrant crypts in the distal intestinal tract of male F344 rats.

Amines↗
PubMed1993

Inhibitory effect of Bifidobacterium longum on colon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline, a food mutagen.

The inhibitory effect of lyophilized cultures of Bifidobacterium longum on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced carcinogenesis was investigated in male and female F344 rats. Beginning at 5 weeks of age, male and female rats were divided into various experimental groups and fed one of the high-fat, semipurified diets containing 0 and 0.5% lyophilized cultures of B. longum with or without 125 ppm IQ in the diet. All animals were continued on this regimen until the termination of the study. All animals were necropsied during the 58th week. The results indicated that dietary B. longum significantly inhibited the IQ-induced incidence (percentage of animals with tumors) of colon (100% inhibition) and liver (80% inhibition) tumors and multiplicity (tumors/animal) of colon, liver, and small intestinal tumors in male rats. In female rats, dietary supplementation of Bifidobacterium cultures also suppressed the IQ-induced mammary carcinogenesis to 50% and liver carcinogenesis to 27% of those observed in animals fed the control diet, but the differences did not reach a statistical significance at P < 0.05; however, the mammary tumor multiplicity (tumors/animal) was significantly (P < 0.05) inhibited in female rats fed the diet containing Bifidobacterium cultures. These findings suggest that Bifidobacterium supplements in the diet inhibit IQ-induced colon and liver tumors and to a lesser extent mammary tumors in F344 rats.

Animals↗
PubMed1993

Induction of mammary cancer by 6-nitrochrysene in female CD rats.

6-Nitrochrysene (6-NC) is a pollutant generated in diesel exhaust. In order to study its propensity to induce mammary cancer, we injected 6-NC into the mammary glands of female CD rats. 4-Nitropyrene (4-NP), the most active mammary carcinogen among the mononitropyrene isomers, was used as a positive control (K. Imaida et al., Cancer Res., 51: 2902-2907, 1991). A total of 2.04 mumol of each compound in dimethyl sulfoxide was injected into each of the six mammary glands on the left side of weanling rats. The corresponding glands on the right side received injections of dimethyl sulfoxide. The thoracic glands were treated on Day 1 and those located in the inguinal area were treated on Day 2. Rats were sacrificed after 43 wk. 6-NC induced fibroadenomas, adenocarcinomas, and spindle cell sarcomas of the mammary glands in a high percentage of the rats. The numbers of animals with mammary tumors and the numbers of malignant tumors were significantly higher in the group treated with 6-NC than in those receiving 4-NP or dimethyl sulfoxide alone. The results of this study, taken together with those of previous bioassays, demonstrate the remarkable activity of 6-NC as a mammary, colon, and lung carcinogen in rodents.

Animals↗