Identification of the Major Hepatic DNA Adduct Formed by the Food Mutagen 2-Amino-9<i>H</i>-pyrido[2,3-<i>b</i>]indole (AαC)

Pfau, Wolfgang; Schulze, Christian; Shirai, Tomoyuki; Hasegawa, Rhyohei; Brockstedt, Ulrike

doi:10.1021/tx9701182

Cited by 40 publications

(36 citation statements)

References 25 publications

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“…In the major covalent DNA adducts formed from HAAs following metabolic activation, the C8 position of guanine is linked to the exocyclic nitrogen. 19,20 Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) are also present in cooked meats and are formed by the pyrolysis of fat. 15 Intra-prostatic injections of B[a]P have induced malignancies in this gland in rodents.…”

Section: Introductionmentioning

confidence: 99%

Primary cultures of prostate cells and their ability to activate carcinogens

Martin

Cole

Muir

et al. 2002

Prostate Cancer Prostatic Dis

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Differences in the incidence of prostate cancer (CaP) amongst different migrant populations point to causative agents of dietary and/or environmental origin. Prostate tissues were obtained following transurethral resection of the prostate (TURP) or radical retropubic prostatectomy. After surgery, TURP-derived or tumour-adjacent tissue fragments were minced in warm PFMR-4A medium (37 C) and suspensions pipetted into collagen-coated petri dishes. Non-adherent material was removed by washing with fresh medium after 12 h. Adhered cells subsequently reacted positively with monoclonal antibodies to prostate specific antigen (PSA). PSA was also detected in the medium. The genotoxicities of the chemical carcinogens 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), its N-hydroxy metabolite (N-OH-PhIP) and benzo[a]pyrene (B[a]P) in adherent cell populations from different donors (n ¼ 8) were examined. Cells were treated in suspension for 30 min at 37 C in the presence of the DNA repair inhibitors hydroxyurea (HU) and cytosine arabinoside (ara-C). DNA single-strand breaks were detected in cells by the alkaline single cell-gel electrophoresis ('Comet') assay and quantified by measuring comet tail length (CTL) in mm. All three carcinogens induced dose-related increases in CTLs (P < 0.0001) in cells from four donors 24 h post-seeding. However, in cells from a further two donors the genotoxic effects of PhIP, N-OH-PhIP and B[a]P were much less apparent after 48 h than after 24 h in culture. After 96 h in culture, cells from these donors appeared to be resistant to the comet-forming activity of the compounds. However, B[a]P-DNA adducts were still measurable by 32 P-postlabelling for up to 14 days following a 24-h exposure to 50 mM B[a]P in adhered cells from another two donors. This study shows that primary cultures of cells derived from the prostate can activate members of two classes of chemical carcinogens. Further development may provide a robust model system in which to investigate the aetiology of CaP.

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Section: Introductionmentioning

confidence: 99%

Primary cultures of prostate cells and their ability to activate carcinogens

Martin

Cole

Muir

et al. 2002

Prostate Cancer Prostatic Dis

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“…Activated heterocyclic amines are able to form adducts with macromolecules such as protein and DNA. It was shown by 32 P-postlabeling analysis that MeA␣C and A␣C both form one major DNA adduct (N 2 -deoxyguanin-8-yl-compounds) in primary hepatocytes from rats (Pfau et al, 1996(Pfau et al, , 1997. The in vitro metabolism of A␣C in human and rodent hepatic microsomes and the metabolism of MeA␣C in hepatic microsomes from PCB-induced rat have been studied and some of the major metabolites characterized (Raza et al, 1996;Frandsen et al, 1998).…”

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confidence: 99%

“…However, although the in vitro metabolism of ␣-carbolines has been studied, there have only been a very few in vivo studies of ␣-carbolines focused on DNA-adduct formation (Yamashita et al, 1986;Pfau et al, 1997;Snyderwine et al, 1998). Compared with other heterocyclic amines, little is known about the in vivo metabolism of ␣-carbolines.…”

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confidence: 99%

IDENTIFICATION OF METABOLITES IN URINE AND FECES FROM RATS DOSED WITH THE HETEROCYCLIC AMINE, 2-AMINO-3-METHYL-9H-PYRIDO[2,3-b]INDOLE (MeAαC)

Frederiksen¹

2004

Drug Metabolism and Disposition

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ABSTRACT:2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA␣C) is a proximate mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems, MeA␣C can be formed by pyrolyses of either tryptophan or proteins of animal or vegetable origin. In the present study, the in vivo metabolism of MeA␣C in rats was investigated. Rats were dosed with tritium-labeled MeA␣C, and urine and feces were collected over 3 days. The metabolites of MeA␣C were identified by high performance liquid chromatography-mass spectrometry and quantified by liquid scintillation counting. Conjugated metabolites were characterized by enzymatic hydrolyzes with ␤-glucuronidase or arylsulfatase. The data showed that the metabolic pattern of MeA␣C was similar in all rats. About 65% of the dose was excreted in urine and feces, and the major amount of MeA␣C-metabolites was excreted during the first 24 h. Thirty-four percent of the dose was found in the rat urine samples collected to 24 h. In addition to unmetabolized MeA␣C and two phase I metabolites, 6-OH-MeA␣C and 7-OH-MeA␣C, the following conjugated metabolites were identified: MeA␣C-N 2 -glucuronide, A␣C-3-CH 2 O-glucuronide, 3-carboxy-A␣C and 3-carboxy-A␣C-glucuronide, and sulfate and glucuronide conjugates of 6-OH-MeA␣C and 7-OH-MeA␣C. Also, a large amount of a rather unstable compound proposed to be of MeA␣C-N1-glucuronide was found. About 21% of the dose was excreted in feces during the first 24 h, and MeA␣C and 7-OH-MeA␣C were the only compounds identified in feces. Any activated metabolites of MeA␣C were not detected in rat urine or feces.2-Amino-9H-pyrido[2,3-b]indole (A␣C 1 ) and its methyl homolog 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA␣C) are two foodborne mutagenic and carcinogenic heterocyclic amines (Wakabayashi et al., 1992). A␣C and MeA␣C are often referred to as ␣-carbolines and are classified as unpolar heterocyclic aromatic amines. ␣-Carbolines are formed as pyrolysis products of either tryptophan or proteins of animal or vegetable origin (e.g., albumin, casein, or soybean globulin) (Yoshida et al., 1978;Sugimura, 1997). ␣-Carbolines are found in cooked food such as fried meat, chicken, fish, mushroom, and bouillon concentrates (Matsumoto et al., 1981;Gross and Gruter, 1992;Layton et al., 1995;Knize et al., 1997;Skog et al., 1998;Solyakov et al., 1999) and cigarette smoke condensates (Yoshida and Matsumoto, 1980;Matsumoto et al., 1981;Manabe et al., 1990;Wakabayashi et al., 1993). Finally, MeA␣C is also found in wine (Richling et al., 1997). ␣-Carbolines are mutagenic in bacterial test systems (Matsumoto et al., 1977;Nagao et al., 1983). Dietary administration of ␣-carbolines to rodents has shown that they are moderately potent carcinogens (Ohgaki et al., 1984;Tamano et al., 1994;Snyderwine et al., 1998).Like other heterocyclic amines, the metabolism of ␣-carbolines usually follows two different pathways, detoxification and activation. The first step in the metabolism of heterocyclic amines is a phase I hydroxylation catalyzed by cytochrome P450 enzym...

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“…While the in vitro metabolism of amino-a-carbolines has been studied [50,51], the in vivo metabolism of amino-acarbolines has only been described in rats in two recent studies [52,53].…”

Section: In Vivo Metabolismmentioning

confidence: 99%

“…Previously DNA-adducts of the amino-a-carbolines were synthesized by an alternative route, where nitro derivates of the aminoa-carbolines were chemically reduced in the presence of DNA. The major adducts synthesized by this method were characterized as N 2 -(deoxyguanosin-8-yl)-MeAaC (dGMeAaC) and N 2 -(deoxyguanosin-8-yl)-AaC (dG-AaC) [50,58]. Recently, the chemical syntheses of dG-MeAaC and dG-AaC succeeded by using the O-acetylation method (Fig.…”

Section: Dna Adduct Formationmentioning

confidence: 99%

Two food-borne heterocyclic amines: Metabolism and DNA adduct formation of amino-α-carbolines

Frederiksen¹

2005

Mol. Nutr. Food Res.

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The amino-a-carbolines 2-amino-9H-pyrido [2,3-b]indole (AaC) and 2-amino-3-methyl-9H-pyrido- [2,3-b]indole (MeAaC) are two mutagenic and carcinogenic heterocyclic amines formed during ordinary cooking. Amino-a-carbolines can be formed in model systems by pyrolyzing tryptophan or proteins of animal or vegetable origin, furthermore they are found in many cooked foods, such as fish, meat, and chicken. The specific mutagenicity of the amino-a-carbolines are lower in the Ames Salmonella assay than other heterocyclic amines, but in rodent studies the carcinogenicity of the aminoa-carbolines are comparable to other heterocyclic amines. The metabolic pathways of the amino-acarbolines have been studied in vitro and in vivo, and the detoxified phase I and phase II metabolites characterized and quantified. The metabolic activation of the amino-a-carbolines and the formation of DNA-adducts have also been studied. Characteristic for the amino-a-carbolines are that relatively large amounts of these compounds in rat and human hepatic microsomes are activated to potent carcinogenic compounds compared with other heterocyclic amines, but further in vivo studies of the amino-a-carbolines are needed to highlight these indications. In this review, the main characteristics with focus on the metabolism and the DNA-adduct formation of the amino-a-carbolines are described and compared with other heterocyclic amines.

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Identification of the Major Hepatic DNA Adduct Formed by the Food Mutagen 2-Amino-9H-pyrido[2,3-b]indole (AαC)

Cited by 40 publications

References 25 publications

Primary cultures of prostate cells and their ability to activate carcinogens

Primary cultures of prostate cells and their ability to activate carcinogens

IDENTIFICATION OF METABOLITES IN URINE AND FECES FROM RATS DOSED WITH THE HETEROCYCLIC AMINE, 2-AMINO-3-METHYL-9H-PYRIDO[2,3-b]INDOLE (MeAαC)

Two food-borne heterocyclic amines: Metabolism and DNA adduct formation of amino-α-carbolines

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