[2-14C]Caffeine metabolism in control and 3-methyl-cholanthrene induced rat liver microsomes by high pressure liquid chromatography

Bonati, Maurizio; Latini, R.; Marzi, Erika; Cantoni, R; Belvedere, G.

doi:10.1016/0378-4274(80)90077-6

Cited by 30 publications

(4 citation statements)

References 11 publications

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Section: Discussionsupporting

confidence: 62%

“…In the case of theophylline, this process is reported to be mediated by a form of the cytochrome P 450 mono-oxygenase system different from the form responsible for N-demethylation processes (Grygiel & Birkett, 1980. This is supported by the recent observation that the demethylation pathways for caffeine appear to be controlled primarily by forms of the microsomal cytochrome P-450 system preferentially induced by polycyclic aromatic hydrocarbons, e.g., cytochrome P-448, in man (Wietholtz et al, 1981), animals and microsomal preparations (Bonati et al, 1980(Bonati et al, , 1984. It is known that the prior intake of methylxanthines can alter their own disposition (Drouillard et al, 1978;Monks et al, 1979). However, it seems unlikely that differing intakes of the methylxanthines were responsible for the increased excretion of the uric acid derivatives in the elderly since other workers Mitoma et al, 1969) have indicated that any effects on metabolism due to normal intersubject differences in habitual caffeine consumption would likely be eliminated by the 3 day abstention period used in this study.…”

Section: Discussionmentioning

confidence: 87%

“…Its metabolism proceeds primarily via successive N-demethylations to form di-then mono-methylated xanthines, some of which are then oxidized to form uric acids. These metabolic conversions occur primarily in the liver and involve the cytochrome P-450 mono-oxygenase system, with available data suggesting that caffeine is a particularly good substrate for cytochrome P-448 (Wietholtz et al, 1981;Bonati et al, 1980Bonati et al, , 1984. The slow maturation of these enzyme systems affects the metabolite pattern of caffeine in the early period of life in both humans Aranda et al, 1981) and animals (Aldridge & Neims, 1980;Warszawski et al, 1981Warszawski et al, , 1982, and it is of interest to ask whether advanced age might cause a similar alteration of any of these metabolic pathways.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the urinary metabolite profile of caffeine in young and elderly males.

Blanchard¹,

Sawers²,

Jonkman³

et al. 1985

Brit J Clinical Pharma

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The urinary metabolite profile of caffeine was compared in a group of seven healthy young men aged 18‐29 years and in a group of five healthy elderly men aged 66‐71 years. All subjects were given 5 mg/kg doses of caffeine as an aqueous oral solution or an intravenous infusion on two separate occasions in a randomized crossover design. Urine samples were collected for 24 h after dosing and analysed for caffeine and eleven of its metabolites by high‐performance liquid chromatography. The effects of age, route of administration, and order of administration by route on the metabolite profile of caffeine were examined. The route of administration and the order of administration by the two routes were found not to influence the urinary metabolite pattern significantly. The urinary metabolite profile did not vary substantially with age except for the observation that significantly greater amounts of 1‐ methyluric acid, 7‐methyluric acid and 1,7‐dimethyluric acid were excreted by the elderly subjects.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparison of the urinary metabolite profile of caffeine in young and elderly males.

Blanchard¹,

Sawers²,

Jonkman³

et al. 1985

Brit J Clinical Pharma

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“…Since in vivo and in vitro studies (27)(28)(29)(30)(31) have suggested a correlation between caffeine oxidation and the hydrocarbon-inducible P-450s (P4501A family), we examined the role of P-450PA (P450IA2) in caffeine metabolism. In this investigation, we report that 3-demethylation of caffeine is highly correlated with ABP N-oxidation in human hepatic microsomal preparations and that both activities are similarly inhibited by 7,8-benzoflavone and by an antibody to human P-450PA.…”

mentioning

confidence: 99%

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Butler

Iwasaki

Guengerich

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

568

327

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Aromatic amines are well known as occupational carcinogens and are found in cooked foods, tobacco smoke, synthetic fuels, and agricultural chemicals. For the primary arylamines, metabolic N-oxidation by hepatic cytochromes-P-450 is generally regarded as an initial activation step leading to carcinogenesis. The metabolic activation of 4-aminobiphenyl, 2-naphthylamine, and several heterocyclic amines has been shown recently to be catalyzed by rat cytochrome P-450ISF-G and by its human ortholog, cytochrome P-45OPA. We now report that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by cytochrome P-450PA. Caffeine 3-demethylation was highly correlated with 4-aminobiphenyl N-oxidation (r = 0.99; P < 0.0005) in hepatic microsomal preparations obtained from 22 human organ donors, and both activities were similarly decreased by the selective inhibitor, 7,8-benzoflavone. The rates of microsomal caffeine 3-demethylation, 4-aminobiphenyl Noxidation, and phenacetin O-deethylation were also significantly correlated with each other and with the levels of immunoreactive human cytochrome P 450PA. Moreover, a rabbit polyclonal antibody raised to human cytochrome P-450PA was shown to inhibit strongly all three of these activities and to inhibit the N-oxidation of the carcinogen 2-naphthylamine and the heterocyclic amines, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole and 2-amino-3-methylimidazo[4,5-fquinoline. Human liver cytochrome P-45OPA was also shown to catalyze caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin 0-deethylation. Thus, estimation of caffeine 3-demethylation activity in humans may be useful in the characterization of arylamine N-oxidation phenotypes and in the assessment of whether or not the hepatic levels of cytochrome P-450PA, as affected by environmental or genetic factors, contribute to interindividual differences in susceptibility to arylamine-induced cancers.The carcinogenicity of arylamines has been well established in both humans and experimental animals (1). Humans are frequently exposed to arylamines such as 4-aminobiphenyl (ABP), 2-naphthylamine (2-NA), and o-toluidine in mainstream and sidestream cigarette smoke (2) and to mutagenic and carcinogenic heterocyclic arylamines in cooked foods (3). Arylamines are also found in coal-and shale-derived oils (4) and in agricultural chemicals (5), and they are used in a variety of industrial processes (1,6,7).Metabolic N-oxidation of primary arylamines, catalyzed by hepatic cytochromes P-450 (P-450s), is a critical initial activation step leading to carcinogenesis (reviewed in refs. 8 and 9). ¶ Studies with purified rat and rabbit P-450s have shown high specificity for the N-oxidation of 2-acetylaminofluorene, 2-NA, ABP, and several heterocyclic amines to their proximate carcinogenic and/or mutagenic forms by the P450IA2 gene products in various species (8)(9)(10)(11)(12)(13)(14)(15). In humans, the orthologous P-450 (16, 17), termed P-45...

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Hepatologie

Rasenack¹,

Pausch²,

Gerok³

et al. 1981

Verhandlungen Der Deutschen Gesellschaft Für Innere Medizin

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[2-14C]Caffeine metabolism in control and 3-methyl-cholanthrene induced rat liver microsomes by high pressure liquid chromatography

Cited by 30 publications

References 11 publications

Comparison of the urinary metabolite profile of caffeine in young and elderly males.

Comparison of the urinary metabolite profile of caffeine in young and elderly males.

Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Hepatologie

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