The contribution of genetically determined oxidation status to inter‐ individual variation in phenacetin disposition.

Devonshire, HW; Kong, In Deok; Cooper, ME; Sloan, T.P.; Idle, Jeffrey R.; Smith, Richard L.

doi:10.1111/j.1365-2125.1983.tb04980.x

Cited by 32 publications

(4 citation statements)

References 26 publications

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“…Early evidence for genetic variability on CYP1A2 was first noted when a familial defect in O -deethylation, a marker reaction for CYP1A2 , was reported more than four decades ago (Devonshire et al 1983; Shahidi 1967). More recently, it has been shown that monozygotic twins share closer kinetic profile than dizygotic twins for caffeine metabolism, with an estimated heritability of 0.725 (Rasmussen et al 2002).…”

Section: Genetics and Caffeine Responsementioning

confidence: 99%

Genetics of caffeine consumption and responses to caffeine

2010

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Rationale Caffeine is widely consumed in foods and beverages and is also used for a variety of medical purposes. Despite its widespread use, relatively little is understood regarding how genetics affects consumption, acute response, or the long-term effects of caffeine. Objective This paper reviews the literature on the genetics of caffeine from the following: (1) twin studies comparing heritability of consumption and of caffeine-related traits, including withdrawal symptoms, caffeine-induced insomnia, and anxiety, (2) association studies linking genetic polymorphisms of metabolic enzymes and target receptors to variations in caffeine response, and (3) case-control and prospective studies examining relationship between polymorphisms associated with variations in caffeine response to risks of Parkinson’s and cardiovascular diseases in habitual caffeine consumers. Results Twin studies find the heritability of caffeine-related traits to range between 0.36 and 0.58. Analysis of poly-substance use shows that predisposition to caffeine use is highly specific to caffeine itself and shares little common disposition to use of other substances. Genome association studies link variations in adenosine and dopamine receptors to caffeine-induced anxiety and sleep disturbances. Polymorphism in the metabolic enzyme cytochrome P-450 is associated with risk of myocardial infarction in caffeine users. Conclusion Modeling based on twin studies reveals that genetics plays a role in individual variability in caffeine consumption and in the direct effects of caffeine. Both pharmacodynamic and pharmacokinetic polymorphisms have been linked to variation in response to caffeine. These studies may help guide future research in the role of genetics in modulating the acute and chronic effects of caffeine.

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Section: Genetics and Caffeine Responsementioning

confidence: 99%

Genetics of caffeine consumption and responses to caffeine

2010

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“…In this regard, cigarette smoking has been shown to induce hepatic P-450PA levels in human liver and to increase microsomal phenacetin O-deethylase activity (21), which is catalyzed selectively by human P-450PA (16). In addition, a genetic polymorphism for phenacetin O-deethylation has been described, with 5-10% of the population deficient in this activity (22).[The evidence that human P-450PA, the phenacetin 0-deethylase, is the product of the human P450IA2 gene is as follows: antibodies raised to rat P-450ISF-G (P-450IA2) or human P-450PA recognize a single polypeptide in human liver microsomes and inhibit microsomal phenacetin 0-deethylase activity; the level of immunoreactive protein is highly corAbbreviations: P-450, cytochrome P-450; ABP, 4-aminobiphenyl; N-OH, N-hydroxy; 13X, 1,3-dimethylxanthine (theophylline); 17X, 1,7-dimethylxanthine (paraxanthine); 37X, 3,7-dimethylxanthine (theobromine); 137U, 1,3,7-trimethyluric acid; 2-NA, 2-naphthylamine; Glu-P-1, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; Trp-P-2, 3-amino-1-methyl-5H-pyrido [4,3-b]indole. §To whom reprint requests should be addressed.…”

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confidence: 99%

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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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“…Clinical pharmacokinetic investigations and studies with human liver microsomes have indicated that the O-deethylation of phenacetin is impaired among poor debrisoquine hydroxylators (Davies et al, 1981;Devonshire et al, 1983). Presumably, the same isozyme of P-450 in human liver catalyzes the oxidation of both phenacetin and debrisoquine.…”

Section: Discussionmentioning

confidence: 99%

Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism

Larrey¹,

Distlerath²,

Dannan³

et al. 1984

Biochemistry

154

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Genetic polymorphism in oxidative drug metabolism is perhaps best exemplified in the case of debrisoquine 4-hydroxylase activity, where the incidence of deficient metabolism ranges from 1% to 30% in various populations and this defect is also linked to an impaired ability to metabolize a number of other drugs effectively. Sprague-Dawley (SD) rats possess this activity, but females of the DA strain do not, although total cytochrome P-450 (P-450) levels are similar. We have purified, by using debrisoquine 4-hydroxylase activity as an assay, a minor P-450 to electrophoretic homogeneity from male SD rats and designate this as P-450UT-H. P-450UT-H differs from eight other purified rat liver P-450s as judged by peptide mapping and immunochemical analysis and thus appears to be isozymic with these other P-450s. P-450UT-H exhibited considerably more debrisoquine 4-hydroxylase activity than any of the other purified P-450s and, on a total P-450 basis, more than total microsomal P-450. Antibodies raised against P-450UT-H specifically recognized P-450UT-H and inhibited more than 90% of the debrisoquine hydroxylase activity present in SD rat liver microsomes. The level of P-450UT-H in SD rat liver microsomes accounted for less than 10% of the total P-450, as judged by immunochemical quantitation. These assays also indicated that the level of P-450UT-H in female DA rat liver microsomes is only about 5% of that in male or female SD rat liver microsomes, consonant with the view that deficiency of this form of P-450 is responsible for the defective debrisoquine 4-hydroxylase activity in the former animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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The contribution of genetically determined oxidation status to inter‐ individual variation in phenacetin disposition.

Cited by 32 publications

References 26 publications

Genetics of caffeine consumption and responses to caffeine

Genetics of caffeine consumption and responses to caffeine

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.

Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism

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