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R H Adamson

Publications and source records attributed to R H Adamson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Metabolism of food-derived heterocyclic amines in nonhuman primates.

During the cooking of meats, several highly mutagenic heterocyclic amines (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been under study for carcinogenicity in cynomolgus monkeys, and to date, IQ has been shown to be a potent hepatocarcinogen. Concomitantly, the metabolic processing of these HCAs has been examined. Metabolism studies show that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formation of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucuronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeIQx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. The poor activation of MeIQx appears to be due to the lack of constitutive expression of CYP1A2 and an inability of other cytochromes P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx is detoxified in monkeys largely by conjugation with glucuronide at the N-1 position. Although the carcinogenicity of PhIP is not yet known, the metabolic data suggest that PhIP will be carcinogenic in this species. PhIP is metabolically activated in vivo in monkeys by N-hydroxylation, as discerned by the presence of the N-hydroxy-N-glucuronide conjugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies support the importance of N-hydroxylation in the carcinogenicity of HCAs in nonhuman primates and by analogy, the importance of this metabolic activation step in the possible carcinogenicity of dietary HCAs in humans.

Amines↗
PubMed1997

Lymphoma induction by heterocyclic amines in E mu-pim-1 transgenic mice.

The usefulness of transgenic E mu-pim-1 mice bearing in their genome the pim-1 oncogene supplemented with an upstream immunoglobulin enhancer and a downstream murine leukaemia virus long terminal repeat, as sensitive test organisms was studied in two short-term carcinogenicity studies. The mice were fed standard diet Altromin 1314 supplemented either with 0.03% 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) for 7 months or with 0.03% 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) for 6 months. PhIP and IQ are heterocyclic amines formed during cooking of meat and fish and are mutagenic to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver, lung and forestomach carcinogen in mice. We found that transgenic E mu-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to IQ treatment. PhIP feeding of E mu-pim-1 mice not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E mu-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males and a strongly reduced latency period after PhIP treatment compared to non-transgenic mice. Our results suggest that the transgenic E mu-pim-1 mouse may be a useful model for short-term carcinogenicity screening of potential genotoxic carcinogens having the lymphoid system as target tissue. Carcinogens that do not target this tissue, like IQ, however will not be recognised.

Animals↗
PubMed1996

Extrapolation of heterocyclic amine carcinogenesis data from rodents and nonhuman primates to humans.

Twenty different heterocyclic amines have been isolated and identified from cooked foods especially beef, fish, pork and fowl. Other HCAs have also been isolated but their structure remains to be elucidated and new HCAs are likely to be identified in the future. The HCAs are highly mutagenic and all ten HCAs that have been tested for carcinogenic activity, produce tumors in mice and rats. For humans the average daily intake of HCAs is in quantities of 10-20 mg/person/day. The HCAs are procarcinogens and are activated by the cytochrome P450 system especially CYP 1A2. Rodents, monkeys and humans have the capacity to activate HCAs. Studies using hepatic microsomes demonstrated that humans have a greater capacity to activate the majority of HCAs tested than rodents or cynomolgus monkeys. Three HCAs are currently under evaluation in nonhuman primates for carcinogenic activity and one, IQ, is highly carcinogenic inducing primary hepatocellular carcinomas in the majority of cynomolgus monkeys treated. Epidemiological studies, although not definitive, are supportive of an association of HCAs intake to the etiology of human cancer. Risk assessments from animal data show a risk of HCAs to humans in the range of 10(-3) to 10(-4) which is an order of magnitude greater than compounds currently regulated by the U.S. Food and Drug Administration or the Environmental Protection Agency. Taken together evidence from mutagenicity data, activation by various species including humans, carcinogenicity in animals, human consumption data, epidemiological studies and risk assessment, supports the conclusion that HCAs are probable human carcinogens.

Amines↗
PubMed1996

Short-term carcinogenicity testing of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in E(mu)-pim-1 transgenic mice.

The usefulness of transgenic E(mu)-pim-1 mice over-expressing the pim-1 oncogene in lymphoid tissues, as sensitive test organisms was studied in a short-term carcinogenicity study. The mice were fed standard diet Altromin 1314 supplemented either with 0.03% 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) for 7 months or with 0.03% 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) for 6 months. PhIP and IQ are heterocyclic amines formed during cooking of meat and fish and are mutagenic to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver carcinogen and also causes lung tumors and tumors of the forestomach in mice. We found that transgenic E(mu)-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to the IQ treatment. PhIP feeding of E(mu)-pim-1 mice not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E(mu)-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males and a strongly reduced latency period after PhIP treatment compared to non-transgenic mice. Our results suggest that the transgenic E(mu)-pim-1 mouse may be a useful model for short-term carcinogenicity screening of potential genotoxic carcinogens having the lymphoid system as target tissue. The carcinogen IQ which does not have the lymphoid system as a target was not recognized in this model.

Animals↗
PubMed1996

Liver tumors and possible preneoplastic lesions, induced by a food-derived heterocyclic amine in cynomolgus monkeys; a study of histology and cytokeratin expression.

A food-derived mutagenic heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), is a potent hepatocarcinogen in cynomolgus monkeys. In an ongoing carcinogenesis study, 34 out of 40 monkeys dosed with IQ have developed malignant liver tumors. The histology and cytokeratin expression was examined in a total of 94 tumors and non-neoplastic lesions obtained from 34 cases. The majority of the tumors were classified as hepatocellular carcinoma. In some cases, a striking difference in the histological features between individual tumor nodules was suggestive of a multicentric origin. Intrahepatic vascular invasion was seen in 14 (41.2%) and metastases in 6 (17.6%) of the hepatocellular carcinoma cases. There was no evidence of regenerative hyperplasia or fibrosis in the parenchyma of the tumor-bearing livers. Clear-cell foci composed of glycogen-rich hepatocytes were the only macroscopic lesions detected prior to gross tumor development. Other liver lesions included dysplastic hepatocyte foci and areas of proliferating bile ductular like (oval) cells, located around the periportal areas and along the portal tracts. Expression of bile duct type cytokeratin 7 was observed in a few of the oval cells and non-malignant hepatocytes, as well as in some of the hepatocellular carcinoma nodules. This aberrant cytokeratin expression raises questions concerning the histogenesis of the IQ-induced hepatocellular carcinoma.

Animals↗
PubMed1995

Carcinogens in foods: heterocyclic amines and cancer and heart disease.

Carcinogens occur naturally in the foods we eat, including a number of HCAs that have been identified in foods (beef, pork, poultry and fish) as a result of cooking. These compounds are formed during the normal cooking process by the reaction of creatine with various amino acids. The HCAs have been identified as a result of their high mutagenic activity in the Ames test. The HCAs can be separated into two types, the nonimidazole and the imidazole type, the latter of which is the predominant type present in Western foods. Both types of HCAs have been found to be carcinogenic in rodent bioassays. Of the three imidazole compounds presently under evaluation in nonhuman primates, IQ has been found to be a potent carcinogen, inducing hepatocellular carcinoma in a majority of the animals in approximately one-seventh of their life span. In addition, a high proportion of the nonhuman primates also had focal IQ-induced myocardial lesions as observed by both light and electron microscopic findings. This information, along with other toxicology data on the HCAs, much of which is cited in this paper, allows the inference to be made that HCAs may be a risk factor for both cancer and cardiovascular disease in humans.

Amines↗
PubMed1995

Visualization of endothelial clefts and nuclei in living microvessels with combined reflectance and fluorescence confocal microscopy.

OBJECTIVE: The cellular basis for spatial heterogeneity along postcapillary venules in their response to inflammatory mediators is not understood. To study permeability regulatory processes on an individual cell basis in intact microvessels, we developed methods to delineate individual endothelial cells within living, single perfused microvessels. METHODS: Individual postcapillary microvessels in the mesenteries of frogs and hamsters were perfused with chloride-free Ringer's solutions containing AgNO3 (0.1 g per 100 ml) for 5--10 s. Vessels were immediately flushed with Ringer's solution containing serum albumin and some vessels subsequently perfused with the fluorescent nucleic acid stain YO-PRO-1 (1 microM) for 10-15 min. Vessels were imaged in situ using laser scanning confocal microscopy. A reflectance image from silver precipitate in the endothelial clefts and a fluorescence image of the nuclei were simultaneously recorded. Stacks of confocal images were merged and used to reconstruct the three-dimensional orientation of endothelial cells. Hydraulic conductivity of some frog mesenteric venular vessels, measured before and after perfusion with AgNO3, was used to assess the integrity of the vessels. RESULTS: The endothelial cell clefts were delineated with a very fine, readily imaged precipitate of silver. Hydraulic conductivity measured after AgNO3 perfusion in frog mesenteric venular microvessels was not significantly different from control. Vessels showed a slight reduction in reactivity to inflammatory stimuli. The three-dimensional pattern of endothelial cells in the living vessels was imaged. CONCLUSIONS: Combining confocal microscopy with silver staining in single perfused microvessels was shown to be an effective means to delineate the three-dimensional pattern of endothelial cells forming microvessel walls. It enables further study of the vascular structure and function relationships at the individual cell level in intact microvessels.

Animals↗
PubMed1995

Metabolic processing and disposition of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in nonhuman primates.

The metabolic processing and disposition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), three heterocyclic amine mutagens and carcinogens derived from cooked food, was examined in cynomolgus monkeys. IQ is an established hepatocarcinogen in cynomolgus monkeys; however, the carcinogenicity of MeIQx and PhIP is not yet known. IQ was extensively metabolized with little parent compound excreted in urine. Urinary metabolites of IQ arise from a combination of cytochrome P-450 mediated N-demethylation, N-hydroxylation, or ring oxidation at the C-5 position and conjugation with sulfate or glucuronide. IQ was also conjugated at the exocyclic amino group forming IQ-sulfamate and IQ-N-glucuronide. Enteric bacteria biotransformed IQ and its N-demethylated metabolite to 7-oxo-IQ and N-demethyl-7-oxo-IQ, respectively. N-Hydroxy-IQ-N-glucuronide was found in urine of monkeys indicating that metabolic activation via cytochrome P-450-mediated N-hydroxylation occurs in vivo and supporting the theory N-hydroxy-IQ plays a role in the initiation of IQ-induced hepatocarcinogenesis. At least eight urinary metabolites of MeIQx were seen in monkeys fed MeIQx. As was found with IQ, metabolites of MeIQx arise from conjugation with sulfate and glucuronide at the exocyclic amino group, and by cytochrome P-450 mediated oxidation at the C-5 position followed by conjugation with sulfate or glucuronide In contrast to IQ, a significant amount of the dose of MeIQx was excreted unchanged in the urine of monkeys. PhIP was extensively metabolized with a predominant route of metabolism being cytochrome P-450-mediated 4'hydroxylation followed by sulfate conjugation to form PhIP-4'-sulfate. No sulfate conjugation at the exocyclic amino group of PhIP was observed. An N-hydroxy-PhIP-N-glucuronide was also found in urine and bile indicating that metabolic activation of PhIP via N-hydroxylation occurs in vivo in monkeys and suggesting that PhIP may ultimately be carcinogenic to monkeys.

Animals↗
PubMed1995

Possible relationship between tissue distribution of DNA adducts and genotoxicity of food-derived heterocyclic amines.

During the past decade and a half, a number of potent mutagens belonging to the class of heterocyclic aromatic amines (HCA) have been isolated and identified from cooked fish, beef, fowl and other meat, and from beef extracts. Several of these HCA mutagens have also been found to be carcinogenic in rodent bioassays, and one of these compounds, 2-amino-3-methylimidazo-[4,5-f]-quinoline (IQ), has recently been found to cause hepatocellular carcinoma in cynomolgus monkeys. The potential etiological role of these mutagens and carcinogens in human cancer prompted us to evaluate the genotoxicity of these compounds in both nonhuman primates and rodents, with particular emphasis on the formation and tissue distribution of DNA adducts. We selected three compounds for this study based on several factors including chemical structure, mutagenic activity in vitro, concentration in cooked food, and carcinogenic activity in the rodent test system. These were IQ, 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP). To maximize the sensitivity of the DNA adduct measurements, we have employed the 32P-postlabeling method to analyze levels and tissue distribution of DNA adducts derived from IQ 8-MeIQx, and PhIP. We have measured DNA adduct formation for all three compounds in various tissues and white blood cells of monkeys following both acute and chronic administration. Both IQ and PhIP form high levels of adducts in a number of organs, particularly liver, kidney, and heart. In contrast, administration of 8-MeIQx to the cynomolgus monkeys results in the formation of only low adduct levels with many tissues showing no detectable levels of adducts. Studies in rodents have also shown that IQ and PhIP from DNA adducts in a number of organs in addition to those that are targets for carcinogenic effects of these agents. Although high DNA adduct levels of HCA are generally found in target organs for HCA induced carcinogenesis the widespread distribution of the adducts in organs not associated with the carcinogenic effects suggest that HCA exposure may be a possible etiological factor in cardiovascular diseases and other degenerative ailments.

Amines↗
PubMed1995

Studies on the carcinogenic and myocardial effects of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in nonhuman primates.

The heterocyclic aromatic amine 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) is one of three heterocyclic amine mutagens currently being evaluated for carcinogenic activity in nonhuman primates, primarily cynomolgus monkeys. IQ was administered by gavage five times a week at doses of 10 or 20 mg/kg. Thus far IQ induced tumors in 50 percent of the monkeys at the 10 mg/kg dose and in 85 percent of the monkeys at the 20 mg/kg dose. Because H and E sections of the myocardium from IQ-treated animals demonstrated inflammatory infiltrate and studies of IQ-DNA adducts in monkeys, by the 32P-postlabeling method, showed high levels of adducts in the heart a systematic study of cardiac pathologic changes associated with chronic administration of IQ was undertaken. Both light and electron microscopic abnormalities were seen. The possibility exists that heterocyclic aromatic amines may be etiologic factors for human cancer and myocardial disease.

Administration, Oral↗
PubMed1995

Laparoscopy as a means of monitoring liver tumor induction in nonhuman primates.

Nonhuman primates are not commonly used in the study of carcinogenesis. For several years, the National Cancer Institute (NCI) has funded a large study to evaluate the relative susceptibility of primates to the effects of several known rodent carcinogens, various cancer chemotherapeutic agents, and several food additives/contaminants, such as cyclamate, saccharin, and aflatoxin. The current colony is comprised of over 300 macaque monkeys which have received a particular test material beginning shortly after birth and continuing for periods of at least 10 years or until tumor is detected. In 1985, a study of the potential carcinogenic effect of the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was initiated. Subsequently, studies on two other heterocyclic aromatic amines were initiated, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) in 1988 and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in 1990. Tumors have been induced thus far only by IQ, and this data will be presented by Dr. Richard Adamson, while the detailed pathology of the neoplasms will be presented by Dr. Unnur Thorgeirsson. Palpation of the liver and monitoring of liver enzymes are not effective means for detecting early evidence of liver tumor. Laparoscopy, on the other hand, can be done easily and quickly and is an effective means of visualizing the liver and for obtaining samples of liver and suspected tumor tissue. Repeated laparoscopic examinations using videotape to document the size, location, and appearance of developing tumors allow more precise monitoring of the carcinogenic process.

Animals↗
PubMed1995

Histopathology of IQ-induced hepatocarcinogenesis in nonhuman primates.

This study describes histopathological findings in 26 nonhuman primates (cynomolgus and rhesus monkeys) with liver tumors after dosing with IQ for time periods of 27 to 72 months. In most of the cases 2-5 well-defined tumor nodules were present in the liver at the time of autopsy. In 5 cases there were numerous nodules occupying most of the liver. Intrahepatic vascular invasion was observed in 14 cases, and lung metastases in 6 cases. The histology of 72 nodules from 21 cases with well-defined tumors and the 5 cases with massive involvement was studied. The majority of the tumors represented well to moderately well-differentiated hepatocellular carcinoma (HCC). Trabecular pattern was most common, followed by solid and pseudoglandular patterns. Five nodules displayed poorly differentiated pleomorphic variant of HCC with large, often multinucleated, tumor cells. Spindle cell and clear cell variants of HCC were seen in one nodule each. Two nodules were classified as cholangiocarcinomas. Immunostaining for cytokeratins 7 and 19 did not prove to be reliable markers for tumors of bile duct origin, since they were also expressed in some of the poorly differentiated HCC. The most common microscopic finding of the noncancerous portions of the liver were clear cell foci, composed of large, glycogen rich hepatocytes with small eccentric nuclei. Other lesions commonly found were dysplastic hepatocyte foci around the central veins and proliferating bile ductular-like (oval) cells along the portal areas and portal tracts.

Animals↗
PubMed1994

Tumor incidence in a chemical carcinogenesis study of nonhuman primates.

This report covers a 32-year period of an ongoing chemical carcinogenesis study in nonhuman primates, which was initiated by the National Cancer Institute in 1961. Autopsy records of 373 breeders and normal controls showed very low incidence of spontaneous malignant tumors in cynomolgus (1.5%) and rhesus (2.8%) monkeys, but considerably higher incidence in African green monkeys (8%). A large number of substances including a variety of food additives, food components, environmental contaminants, N-nitroso compounds, "classical" rodent carcinogens, antineoplastic agents, and immunosuppressive agents have been evaluated for long-term carcinogenic activity. Food components tested which are probably most relevant to human exposure are the artificial sweeteners, cyclamate and saccharin. After 22 years of continuous dosing, neither cyclamate nor saccharin have shown any evidence of carcinogenic effects. Similarly, the tumorigenic potential of arsenic and DDT was negligible after dosing for 15-22 years. In contrast, the fungal food contaminants, aflatoxin B1 (AFB1) and sterigmatocystin (SMT), were found to be potent hepatocarcinogens. AFB1 also induced adenocarcinomas of the pancreas, osteosarcomas, and other tumors. Also, the aglycone of cycasin, MAM acetate, induced a variety of tumors, but primarily hepatocellular and renal cell carcinomas. The compounds most recently introduced into the colony include three heterocyclic amines present in cooked meat. One of these compounds, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) has proven to be one of the most potent hepatocarcinogens in the history of the monkey project, inducing malignant liver tumors in 65% of animals over a 7-year period of exposure. Of the classical rodent carcinogens studied, urethane was the only one which produced malignant tumors in the monkeys. Conversely, all except two of the N-nitroso compounds were carcinogenic. Diethylnitrosamine (DENA) was the most potent and predictable hepatocarcinogen in cynomolgus, rhesus, and African green monkeys. However, when administered intraperitoneally to galagos (a prosimian), DENA induced primarily mucoepidermoid carcinoma of the nasal cavity. N-Methyl-N-nitrosourea (MNU) was the only carcinogen persistently producing tumors in the digestive tract, mostly squamous cell carcinomas of the esophagus. Among the antineoplastic and immunosuppressive agents, procarbazine (MIH) was the only unequivocal carcinogen, with a 33% tumor incidence, causing acute nonlymphocytic leukemia in most of the cases.

Animals↗
PubMed1994

DNA adduct levels of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in tissues of cynomolgus monkeys after single or multiple dosing.

DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), a heterocyclic amine derived from cooked meat, were measured by the 32P-postlabeling method in tissues of cynomolgus monkeys given PhIP. Monkeys received either a single dose of PhIP (20 mg/kg orally) or nine daily doses of PhIP (20 mg/kg orally, days 1-5 and 8-11) and tissue samples were obtained 24 h after the last dose. Over 28 different tissues were examined for PhIP-DNA adducts. Adducts were detected in all tissues examined except the fat and bone marrow. After a single dose, adduct levels (mean value/10(7) nucleotides, n = 2 monkeys) were highest in the liver (2.1), followed by the lung (1.7), gall bladder (1.7) and pancreas (0.9). Low adduct levels were detected in the brain and aorta (0.06 and 0.02 respectively). Following multiple doses of PhIP, adduct levels (mean value/10(7) nucleotides +/- SE, n = 3 monkeys) were highest in the heart (5.7 +/- 2.0) followed by the liver (3.8 +/- 0.8), submandibular gland (2.7 +/- 1.8) and pancreas (2.2 +/- 0.5). Comparison of the adduct levels after a single dose with those found after multiple doses indicates that accumulation of PhIP-DNA adducts occurred in certain tissues. Adduct levels in liver, pancreas, kidney, small intestine and colon increased about 1.5- to 2.4-fold. PhIP-DNA adduct levels in submandibular gland and brain increased 4- to 5-fold. Adduct levels in heart increased 10-fold and levels in the aorta increased 31-fold. Adducts in white blood cell DNA increased with daily dosing for 9 days. No apparent changes in adduct levels were seen in the lung, stomach, bladder, muscle and spleen. The wide distribution of PhIP-DNA adducts and their presence in white blood cells suggests that there is transport of reactive metabolites from the liver to extrahepatic tissues. The relatively high adduct levels in the gall bladder in comparison with the liver suggests biliary excretion and possible reabsorption of reactive metabolites. The presence of DNA adducts in tissues implicates PhIP as a potential carcinogen in non-human primates. The possibility that PhIP-DNA adducts in tissues such as the heart and aorta may have toxicological consequences is discussed.

Administration, Oral↗
PubMed1994

p53 gene mutation in hepatocellular carcinoma induced by 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of several heterocyclic amines formed during the cooking of proteinaceous foods. IQ is a potent carcinogen in rodent bioassays and causes a high incidence of hepatocellular carcinomas in nonhuman primates. We examined 20 hepatocellular carcinomas (HCCs) from nonhuman primates for mutations of the p53 gene using polymerase chain reaction-single strand conformational polymorphism analysis. Mutations in the p53 gene were detected in 4 of 20 HCCs (20%) with 3 showing G-to-T transversions and one a G-to-A transition. Three of these mutations were observed in codons 175 and 248 that are known mutational hot spots in human cancers. These data indicate that part of the IQ-induced HCCs in nonhuman primates may involve inactivation of the p53 gene and suggest that IQ and possibly other heterocyclic amines may participate in human carcinogenesis by a similar mechanism.

Animals↗
PubMed1994

Induction of hepatocellular carcinoma in nonhuman primates by the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated for carcinogenic effects in macaques, primarily cynomolgus monkeys. IQ was administered by gavage five times a week at doses of 10 or 20 mg/kg. IQ induced hepatocellular carcinoma in 55% of the animals at the low dose and in 95% of the animals at 20 mg/kg. The average latent period at the high dose level was 43 months and that at the low dose was 60 months. Generally, the tumor nodules exhibited a well- to moderately well-differentiated hepatocellular carcinoma, and a trabecular pattern was most frequently seen. Pulmonary metastases were also found in several of the monkeys. Thus, IQ is a potent carcinogen in nonhuman primates and is a potential carcinogen for humans.

Animals↗