Exposure to heterocyclic amines.

Abstract

Many mutagenic heterocyclic amines (HAs) have been isolated from cooked foods and pyrolysates of amino acids and proteins, and the carcinogenicity of 10 of these HAs in rodents and of 1 in monkeys has been reported. Quantification of these carcinogenic HAs in various kinds of cooked foods indicated that the level of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was highest (0.56-69.2 ng/g), that of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was second highest (0.64-6.44 ng/g), and those of other HAs were 0.03-2.50 ng/g. Heterocyclic amines were found in urine samples of 10 healthy volunteers consuming a normal diet, but HAs were not detectable in urine samples of three patients receiving parenteral alimentation. These results strongly suggest that humans are continuously exposed to HAs derived from food in the normal diet. Based on quantitative data on the levels of HAs in cooked foods and urine samples, the daily exposures to PhIP and MeIQx were estimated to be 0.1-13.8 micrograms and 0.2-2.6 micrograms per person, respectively. These levels of carcinogenic HAs are in the same range as those of other carcinogens such as N-nitrosodimethylamine and benzo[a]pyrene to which humans are exposed.

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

“…Statistical significance was determined by Fisher's exact probability test. 1 Adenocarcinoma, tubular adenocarcinoma and mucinous adenocarcinoma.-2 Total tumors, adenoma and adenocarcinoma.-3 Significantly different from the 0-10 ppm groups at p < 0.005.- 4 Significantly different from the 0.001 and 0.1 ppm groups at p < 0.05.- 5 Significantly different from the 0-10 ppm groups at p < 0.05.- 6 Significantly different from the 0-10 ppm groups at p < 0.0001.…”

“…25 Actually, humans are only exposed to the carcinogen at quite low-dose levels, albeit continuously. 5,6 Besides, even high doses of PhIP alone (without any other carcinogens) induce relatively low tumor yields in rats. Thus, it seems difficult to evaluate actual colon carcinogenicity of lowdose PhIP alone in animal experimental models, especially if relying on quantitative analysis of neoplasms.…”

“…5 It has been detected in the urine of healthy volunteers, including both smokers and nonsmokers. 5,16 The initial step for its bioactivation is N-hydroxylation, catalyzed mainly by cytochrome P450 1A2 (CYP1A2) in the livers of both humans and rats, and CYP1A2 activity in the liver is 19-fold higher in humans than in the rat. 17 This N-hydroxy-PhIP can reach the intestinal mucosa via the blood and then be bioactivated by N-acetyltransferase (NAT) or phenol sulfotransferase to N-acetoxy-or N-sulfonyloxy-esters, especially by NAT2.…”

“…4 One focus of attention has been food-derived heterocyclic amines (HCAs) generated in cooking processes that have proved to be carcinogenic in rodent species. 5,6 HCAs are highly mutagenic 6 and genotoxic carcinogens that are generally thought to have no threshold in exerting their carcinogenic potential, which was postulated to exhibit dose dependence in vivo. 3 However, in practice, low-dose administration has not necessarily led to cancer development in the rat liver.…”

“…15 PhIP is found at a concentration range of 0.56-69.2 ng/g in cooked foods and daily intake is estimated to be 0.1-13.8 mg/person. 5 It has been detected in the urine of healthy volunteers, including both smokers and nonsmokers. 5,16 The initial step for its bioactivation is N-hydroxylation, catalyzed mainly by cytochrome P450 1A2 (CYP1A2) in the livers of both humans and rats, and CYP1A2 activity in the liver is 19-fold higher in humans than in the rat.…”