Heterocyclic Amines (HCA)

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Heterocyclic amines (HCAs) contain at least one heterocyclic ring (with atoms of at least 2 different elements) and one amine group, attached to the heterocyclic ring. Major groups of HCAs are Carbolines (indoles), Pyrrolidines, Pyrroles (in Hb and vitamin B12), Pyridines (vitamin B3 and B6) and Pyrimidines (vitamin B1), including Purines (adenine, guanine).

Many HCA are harmless, or even beneficial (eg vitamins), whereas others, created by cooking, may cause cancer or influence brain functioning.


Mutagenic HCA in cigarette smoke

Besides carcinogens such as polycyclic aromatic hydrocarbons (eg Benzo(alpha)Pyrene) and nitrosamines (eg N-Nitrosodimethylamine), the following HCA are a few of the HCA found (besides in diesel exhaust [1]) in cigarette smoke:

But exactly the same compounds are also found in cooked foods:

In fact, "the A alpha C and MeA alpha C contents of 1 g of grilled beef were 650.8 ng and 63.5 ng, respectively. They were equivalent to those of about 8 cigarettes. The smoke condensate of a blended cigarette (A) contained 79.7 ng of A alpha C and 6.2 ng of Me alpha AC ". [18]

Carcinogenic HCA in cooked foods

HCAs form when amino acids (particularly serine, tryptophan and glutamic acid[19]) are heated, particularly in the presence of creatinine (in meat and fish). HCA concentration is associated with meat doneness [20] and cooking temperature [21][22]. Grilling yields over 10-fold more HCAs than cooking. [23] The darker the surface colour of the meat, the higher the HCA concentrations [24]. Antioxidants (present in the food when cooked) inhibit HCA formation [25], particularly phenols (as in olive oil, tea) [26]. Enzymes in the human liver (and tongue [27]) activate those HCAs [28]: HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s (as humans age, the activity of P450s decreases[29]), and further converted to ester forms (with acetic acid, sulfuric acid, proline) by acetyltransferase and sulfotransferase (dietary fat increases these enzyme activities[30], but fatty acids (and fiber[31]) may also bind and inactivate HCAs[32]). Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases [33], which actually exist in human tissues, and may be involved in human cancer development [34] Adding PhIP to the diet at a concentration of 400 ppm (parts per million) for 1 year induced carcinomas in 47% of female rats. 100 ppm of PhIP for 2 years yielded the same incidence. [35] There is a linear relation between DNA adducts in the liver and doses of MeIQx fed to rats [36]. The carcinogenic effects of HCAs are additive or synergistic, particularly at low doses [37][38][39][40].

These 10 HCA have been shown to be carcinogenic in rats and/or mice when administered in the diet (for 1 to 2 years) at concentrations of 100-800 ng / gram (ppm) : IQ, MeIQ, MeIQx, PhIP, Trp-P-!, Trp-P-2, Glu-P-1, Glu-P-2, AalphaC and MeAalphaC.

Now consider human daily intake, not for 2 years, but for a lifetime. These amounts were found in cooked foods (in ng / gram cooked food) [41]:

  • 0.2 ng IQ
  • 0.03 ng MeIQ
  • up to 6 ng MeIQx
  • up to 69 ng PhIP
  • up to 0.2 ng Trp-P-1
  • 0.2 ng Trp-P-2
  • up to 2.5 ng AalphaC
  • 0.2 ng MeAalphaC

Human tissues have been shown to be vulnerable to these HCAs [42][43][44][45]. Even very low doses of HCAs may cause cancer [46]. Substitutions on their structural rings may block detoxication reactions [47]. Epidemiological studies show associations between HCA intake and breast cancer, colon cancer, prostate cancer and pancreatic cancer [48]. Diet and nutrition may be responsible for 60% of the total cancer incidence for women and greater than 40% for men.[49] The capacity of detoxification mechanisms may account for several hundred-fold difference in mutagenicity of HCAs.[50] Bacteria from a healthy intestinal microflora may (irreversibly) bind such HCAs (50% of PhIP, almost 100% Trp-P-2) [51]

Mutagenic HCA in cooked foods

The IQ-type HCAs are derived from amino acids and from creatinine in raw meat and fish, or sugars additionally. Non-IQ-type HCAs are obtained by heating tryptophan (indoles / gamma-carbolines) or glutamic acid (imidazoles).

  • 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; in broiled sardines, cooked beef, fried fish) [52]
  • 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx; broiled sardines)[53]
  • 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]) [54]
  • 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ; in fried fish) [55][56][57]
  • 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx; in various cooked foods) [58]
  • 2-amino-3,4,7,8-tetramethylimidazo[4,5-f]quinoxaline (TriMeIQx; in griddled bacon) [59]
  • 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx; in fried fish [60] and beef extract [61]}
  • 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx; in roasted eel) [62] (creatinine + glycine + glucose[63])
  • 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx; in beef extract) [64]
  • 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx; in beef extract) [65]
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP; in cooked meat and fish) [66][67]
  • 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) [68]
  • 2-amino-1-methyl-6-(4-hydroxyphenyl)imidazo[4,5-b]pyridine (4'-OH-PhIP; in broiled beef) [69] (creatine + tyrosine + glucose)
  • 2-amino-n,n-dimethylimidazopyridine (DMIP) [70]
  • 2-amino-n,n,n-trimethylimidazopyridine (TMIP) [71]
  • 2-Amino-5-phenylpyridine (2-APP or Phe-P-1)[72] (its ultimate acetoxy reactive species) [73]
  • 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) [74] in broiled beef[75] and broiled fish (13.3 ng of Trp-P-1 / g. broiled sardines)[76]
  • 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) [77] in cooked beef and fish[78](13.1 ng of Trp-P-2 / g. broiled sardines.)[79]; also inhibits L-Dopa synthesis (similar to other alpha- and gamma-carbolines, and PhIP) [80]
  • 2-amino-9H-pyrido[2,3-b]indole (A alpha C; soybean globulin and cooked meat) [81]
  • 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C; soybean globulin, cooked meat, fried fish [82][83][84]. About 17% is activated to mutagenic N2-hydroxy-MeA alpha C [85].
  • 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1 (a delta-carboline); in roasted mackerel and pork) [86] HCAs are eventually metabolized into less mutagenic compounds, such as N-acetyl-Glu-P-1 [87]
  • 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2 (a delta-carboline); in cooked salmon [88] and Worcestershire sauce) [89]
  • methyl-2-methylamino-IH,6H-pyrrolo[3,4-f]benzimidazole-5,7-dione (Cre-P-1) [90]

Neuro-active HCAs; natural ones and in cooked foods

In the human body (and human milk [91]), various endogenous beta-carbolines (eg tetrahydro-beta-carboline (tryptoline), 6-methoxytetrahydro-beta-carboline, tetrahydro-harman, harman, harmalan [92][93]) act on the Benzodiazepine receptors as neurotransmitters (regulating behavioral habituation [94], appetite [95] and modulating acetylcholine release [96][97]), and are monoamine oxidase (MAO) inhibitors [98]. beta-Carbolines may be anti-mutagenics, anti-genotoxic [99] and often associated with (acetyl)cholinesterase inhibition [100][101]

Various foods, such as fish, meat and fruits naturally also contain beta-carbolines, and cooking may dramatically increase their level and form different ones, that may be moderately naturally present in other foods. When heating tryptophan, various beta-carbolines (indoles) are formed [102]), such as harman and norharman. [103] Studies show long-term retention of these specific neurotoxic beta-carbolines in brain neuromelanin [104]. Nitrosation (in the presence of nitrite) of beta-carbolines generally produces mutagenics [105], but also reaction with aniline may produce mutagenics [106][107]. Unlike 'normal' beta-carbolines (such as harman and norharman), tetrahydro-beta-carbolines are generally anti-oxidants. [108] Reaction of tryptophan with aldehydes (benzaldehyde, vanillin, syringaldehyde, salicylaldehyde, anisaldehyde; particularly in fermented foods[109]) may already result in beta-carbolines at 70°C [110], and with the addition of glucose, copper and iron ('fortified foods'), beta-carbolines may already form at 40°C. [111]

beta-Carbolines in cooked foods

Cooking may induce complex beta-carbolines. All simple beta-carbolines foods have been tested for, were actually present in cooked foods, and yet, many simple beta-carbolines have not been tested for occurence in cooked foods. The following (simple and complex) beta-carbolines have been identified.

  • Norharman(e) (9H-pyrido[3,4-b]indole = β-carboline) in cigarette smoke, cooked meat [112][113][114], cooked fish, toasted bread [115] and coffee [116] is a neurotoxin [117] has synergistic effects with Trp-P-2 [118] and may contribute to idiopathic Parkinson's disease [119]). Endogenous norharman formation is about 50-100 ng per kg bodyweight, whereas total daily dietary exposure is estimated at max 4000 ng / kg. [120]
  • Harman(e) (1-methyl-β-carboline) in cigarette smoke, cooked meat [121], particularly chicken[122], cooked fish, toasted bread [123][124] and coffee [125]. Harman is a a tremor-producing neurotoxin. Meat consumption is higher in men with essential tremor [126]. Harman also impairs learning [127][128] through the nicotinic cholinergic system [129] and alters behaviour [130]). Daily total dietary exposure is estimated at max 1000 ng/kg bodyweight (daily endogenous formation 20 ng/kg)[131]
  • Harmine (7-methoxy-1-methyl-β-carboline); in smoked salmon and soft cheese [132]; genotoxic [133], induces dopamine release [134], inhibits the enzymes MAO-A (which may cause accumulation of mono-amines), DYRK1A, CLK1, CLK2 [135], phosphodiesterase [136] and acetylcholinesterase [137]) UV light exposure increases toxicity of harmine.[138]
  • Harmaline (7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole) in beer, coffee and cheese [139]; psychoactive, induces dopamine [140] and nitric oxide release and inhibits phosphodiesterase [141], acetylcholinesterase [142] and MAO-A.
  • Harmalol (1-Methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-7-ol) in beer, coffee and cheese [143]; induces melanogenesis [144] interferes with DNA synthesis [145] and inhibits the enzymes acetylcholinesterase and butyrylcholinesterase. [146]
  • 1-acetyl-β-carboline-3-carboxylic acid (in ketchup and heated tomato concentrate[147]; selectively decreases responding [148] and may interact with other beta-carbolines[149])
  • 3,4-dinitro-1-methyl-β-carboline-3-carboxylic acid in soy sauce and beer [150]
  • Tryptoline (1,2,3,4-tetrahydro-β-carboline) in sausages[151]; a MAO-A inhibitor [152])
  • 1-furyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in soy sauce and bean paste [153]
  • 1-(5’-hydroxymethylfuryl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in bean paste [154]
  • 1-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in smoked foods. [155]
  • 1-pentahydroxypentyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in fruit- and vegetable- (heat-involved) products (jams etc) [156]
  • Flazin (1-(5'- hydromethyl-2'-furyl)-β-carboline-3-carboxylic acid) in soy sauce; cytotoxic [157] and induces quinone reductase (QR) activity [158])
  • Perlolyrin (in soy sauce [159]; weakly cytotoxic [160] induces quinones reductase (QR) activity [161])
  • 1-(1,3,4,5-tetrahydroxypent-1-yl)-β-carboline
  • 1-(1,4,5-trihydroxypent-1-yl)-β-carboline
  • 1-(1,5-dihydroxypent-3-en-1-yl)-β-carboline; in various foods, but particularly ketchup, soy sauce, and fish sauce.[162].
  • 1-(1,4-dihydroxybutyl)-β-carboline
  • 1-(1,3,4-trihydroxybutyl)-β-carboline (tryptophan + xylose) [163]

beta-Carbolines in fruits and plants

Some beta-carbolines may be natural in some raw foods, whereas the product of cooking in others (or in the same food). MTCA is naturally present in fruits; oranges, mandarins, bananas, pears etc. As fruit ripens and gets softer during storage, MTCA levels increase. [164] Besides fruits, THCA is naturally present in raw fish, and raw meat (and humans) and partly converted in MTCA due to cooking, whereas the levels of both THCA and MTCA (and mutagenic harman and norharman) are increased by cooking. [165][166] Tetrahydro-beta-carbolines generally cannot induce mutation. [167]

  • 1-methyltryptoline (1-methyl-1,2,3,4-tetrahydro-β-carboline = tetrahydro-harman) in sausages [168], tomato and kiwi; antioxidant [169]and MAO-A inhibitor [170])
  • THCA (1,2,3,4-Tetrahydro-beta-carboline-3-carboxylic acid) in fruits [171], raw (and cooked) fish and meat [172], toasted bread, beer, cider, wine vinegar, soy and tabasco sauce and blue cheese. [173]
  • MTCA (1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid) acting as antioxidant [174] in fruits [175][176], cooked fish [177], soy sauce [178], vinegar [179], wine, beer, yoghurt, tabasco, blue cheese [180] and fermented garlic. [181] MTCA is a xanthine oxidase (XO) inhibitor, thus inhibiting uric acid formation [182] MTCA is (co)mutagenic in the presence of nitrite, which is inhibited by components present in oranges.[183]
  • MTCdiC (1-methyl-1,2,3,4-tetrahydro-β-carboline-1,3-dicarboxylic acid) in aged garlic (not raw[184]); a superoxide scavenger [185])
  • 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline in alcoholic beverages [186], bananas, pineapple and tomato; acting as an antioxidant [187]
  • 1-(2-pyrrolidinethione)-3-yl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in fermented radish root. [188]

beta-Carbolines in the seeds of Peganum harmala Also known as Harmal or Syrian Rue.

  • Harmine (7-methoxy-1-methyl-β-carboline)
  • Harmaline (7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole)
  • Harmalan (1-methyl-3,4-dihydro-beta-carboline)
  • Harmol [189]
  • Harmalol (1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-7-ol)
  • Tetrahydroharmine ((7-methoxy-1-methyl-1,2,3,4-tetrahydro-β-carboline)
  • Harmine (methyl-7-methoxy-β-carboline-1-carboxylate)
  • Harmilinic acid (7-methoxy-3,4-dihydro-β-carboline-1-carboxylic acid)
  • Harmanamide (1-carbamoyl-7-methoxy-β-carboline)
  • Acetylnorharmine (1-acetyl-7-methoxy-β-carboline)
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