Inhibition of dietary mutagen activation by methylxanthines

Murray, B. P.; Boobis, Alan R.; Torre, Rafael de la; Segura, Jordi; Davies, Donald S.

doi:10.1042/bst0160620

Cited by 12 publications

(3 citation statements)

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“…Both are known to be substrates for cytochrome P450 IA2-mediated reactions, as are aromatic and heterocyclic amines (19,20). Caffeine has been reported to inhibit the mutagenicity of various heterocyclic amines in Salmonella (15,21,22) However, analysis of urine extracts by HPLC revealed that the concentrations of these methylxanthines in urinary extracts were far too low to account for their inhibitory effect on PhIP mutagenicity, as reported previously (3). An inhibitory effect of unsaturated fatty acids on the mutagenicity of heterocyclic amines and other carcinogens has been reported (23) and their presence in human urine is well documented (24).…”

Section: Discussionmentioning

confidence: 83%

Dietary phenolics as anti-mutagens and inhibitors of tobacco-related DNA adduction in the urothelium of smokers

Malaveille¹,

Hautefeuille²,

Pignatelli³

et al. 1996

Carcinogenesis

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Human urine is known to contain substances that strongly inhibit bacterial mutagenicity of aromatic and heterocyclic amines in vitro. The biological relevance of these anti-mutagens was examined by comparing levels of tobacco-related DNA adducts in exfoliated urothelial cells from smokers with the anti-mutagenic activity in corresponding 24-h urine samples. An inverse relationship was found between the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-mutagenicity by urine extracts in vitro and two DNA adduct measurements: the level of the putatively identified N-(deoxyguanosine-8-yl)-4-aminobiphenyl adduct and the total level of all tobacco-smoke-related carcinogen adducts including those probably derived from PhIP. Urinary anti-mutagenicity in vitro appears thus to be a good indicator of the anti-genotoxicity exerted by substances excreted in urine, that protect the bladder mucosal cells (and possibly other cells) against DNA damage. These substances appear to be dietary phenolics and/or their metabolites because (i) the anti-mutagenic activity of urine extracts (n = 18) was linearly related to their content in phenolics; (ii) the concentration ranges of these substances in urine extracts were similar to those of various plant phenols (quercetin, isorhamnetin and naringenin) for which an inhibitory effect on the liver S9-mediated mutagenicity of PhIP was obtained; (iii) treatment of urines with beta-glucuronidase and arylsulfatase enhanced both anti-mutagenicity and the levels of phenolics in urinary extracts; (iv) urinary extracts inhibited noncompetitively the liver S9-mediated mutagenicity of PhIP as did quercetin, used as a model phenolics. Several structural features of the flavonoids were identified as necessary for the inhibition of PhIP and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxiline mutagenicity. Fractionation by reverse-phase HPLC and subsequent analysis of two urinary extracts, showed the presence of several anti-mutagenic substances and phenolics; more lipophilic phenolics displayed the highest specific inhibitory activity. This suggests that enzymatic conversion of dietary flavonoids into their more lipophilic and anti-mutagenic O-methylcatechol derivatives, as noted for quercetin, may occur in vivo in man. Onion, lettuce, apples and red wine are important sources of dietary flavonoids which are probably responsible for the anti-mutagenicity associated with foods and beverages. After HPLC fractionation of urinary extracts, the distribution profile of anti-mutagenic activity corresponded roughly to that of onion and wine extract combined. Our study strongly suggests that smokers ingesting dietary phenolics, probably flavonoids, are partially protected against the harmful effects by tobacco carcinogens within their bladder mucosal cells. This protective effect of dietary phenolics against the cancer of the bladder (and possibly other sites) should be verified and explored as a part of a chemoprevention strategy.

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Section: Discussionmentioning

confidence: 83%

Dietary phenolics as anti-mutagens and inhibitors of tobacco-related DNA adduction in the urothelium of smokers

Malaveille¹,

Hautefeuille²,

Pignatelli³

et al. 1996

Carcinogenesis

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“…We previously demonstrated that macro-and microcomponents of the diet such as fat, fiber, and plant flavonoids can modify the in vivo genotoxicity of heterocyclic amines by altering their uptake from the gut lumen or their metabolism (12)(13)(14)(15). Another microcomponent of the Western diet, caffeine, has been shown by us and others to inhibit the in vitro conversion of heterocyclic amines to genotoxins (16,17). Caffeine is of particular interest, because its own metabolism is, like MelQx, to some degree dependent on CYP1A2 (18).…”

Section: Introductionmentioning

confidence: 96%

Dietary caffeine reduces the genotoxicity of MeIQx in the host‐mediated assay in mice

Alldrick

Brennan-Craddock

Rowland

1995

Nutrition and Cancer

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The influence of dietary caffeine on the genotoxicity of the cooked food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) was evaluated using the host-mediated assay in mice. For four weeks, BALB/c mice were fed a purified diet with or without caffeine (0.01% wt/wt in the diet). In the host-mediated assay, Salmonella typhimurium TA98 was given intravenously immediately before an oral dose of MeIQx (1.5 mg/kg body wt). After one hour, the mice were killed, the Salmonellae were recovered from the liver, and the number of mutants (his+ revertants) were determined. Consumption of caffeine led to a 47% reduction in the number of mutants induced by MeIQx (p < 0.001). Subsequent in vitro experiments using S. typhimurium TA98 revealed that the capacity of hepatic S-9 fractions from the caffeine-fed mice to covert MeIQx to an active mutagen was reduced by approximately 35%. This effect was not attributable to caffeine in the S-9 preparation. These data suggest that consumption of caffeine modifies MeIQx mutagenicity by altering the spectrum of enzymes involved in its activation.

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“…The biological monitoring of Trp-P-1 and Trp-P-2 in human plasma , and MeIQx in human urine (Murray et al 1989) show that humans are widely exposed to measurable quantities of these compounds. The fact that microsomal fractions of human liver can convert both MeIQx (Murray et al 1988) and 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (McManus et al 1989) to potent mutagens in the Ames Salmonella test, and the fact that N-acetylated metabolic products of Glu-P-1 and Glu-P-2 have been found in human urine, bile, liver and kidney (Kanai et al 1988) indicate that these compounds may be suspect human carcinogens. However, until more information is obtained about the carcinogenicity of these compounds in dose-response studies, including low exposures, and in animal species other than rats and mice, in which their potency is only moderate, and more comprehensive information on their occurrence in foods is available, the potential human cancer risk presented by these compounds will be hard to evaluate.…”

Section: Heterocyclic a M I N E S ( P R O T E I Y Pyrolysis P R O D Umentioning

confidence: 99%

Chemical food contaminants in the initiation of cancer

Tricker

Preußmann

1990

Proc. Nutr. Soc.

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Inhibition of dietary mutagen activation by methylxanthines

Abstract: 1970) J. Rid. C'hem. 245,6649-6656 Kes. Comrnun. 24, 79-84 ( 1 986) Insect Hiochem. 16,749-756 Vol. I6

Cited by 12 publications

References 0 publications

Dietary phenolics as anti-mutagens and inhibitors of tobacco-related DNA adduction in the urothelium of smokers

Dietary phenolics as anti-mutagens and inhibitors of tobacco-related DNA adduction in the urothelium of smokers

Dietary caffeine reduces the genotoxicity of MeIQx in the host‐mediated assay in mice

Chemical food contaminants in the initiation of cancer

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