Caffeine metabolism in a group of 67 patients with primary biliary cirrhosis

Le-Louët, Hervé; Yc, Bechtel; Paintaud, Gilles; Mp, Brientini; Jp, Miguet; Bechtel, P

doi:10.5414/cpp39025

Cited by 17 publications

(23 citation statements)

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“…24 Moreover, in liver microsomes, CYP2A6 has been found to be the principal enzyme involved in hydroxylation of 17X; this activity being highly associated with coumarin 7-hydroxylase activity 20 and coumarin is the most used probe drug for CYP2A6 because of its hydroxylation is specifically catalyzed by CYP2A6, 27 The ratio 17U/17X has been used to assess CYP2A6 in other studies. [21][22][23][24] Another argument supporting that the ratio 17U/17X really measures CYP2A6 activity comes from the lack of influence of tobacco smoking on 17U/17X values found in this study. It is well known that tobacco smoking increases CYP1A2 activity.…”

Section: Discussionmentioning

confidence: 96%

CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives

et al. 2008

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This study was performed to assess the influence of age, sex, smoking, and contraceptive use on CYP2A6 activity. In the metabolism of caffeine, the conversion of 1,7 dimethylxanthine (17X) to 1,7 dimethiylurate (17U) is catalyzed primarily by CYP2A6. CYP2A6 phenotype was determined by the urinary ratio 17U:17X in the interval of 4–5 h after caffeine intake in 179 healthy white Spaniards (102 women and 76 men). There were 99 non-smokers and 80 smokers. Among women, 26 were taking oral contraceptives. The age was the most important predictive factor of CYP2A6 activity ( P < 0.001) with older subjects having higher activity. The influence of the gender was more modest ( P = 0.07) with women exhibiting borderline increased values of the CYP2A6 marker than men. Tobacco smoking did not affect CYP2A6 activity. However, the CYP2A6 marker resulted to be strongly related to the use of oral contraceptives. The women users of oral contraceptives had higher values of CYP2A6 marker than both women not taking oral contraceptives and men ( P < 0.001 in both comparisons). The results indicate that age, oral contraceptive use, and possibly gender should be controlled in epidemiological studies dealing with CYP2A6 activity and its relationship with xenobiotics exposure and genetic or pathological factor.

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Section: Discussionmentioning

confidence: 96%

CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives

et al. 2008

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“…Although previous studies have shown that CYP1A2 activity may be influenced by gender, menstrual cycle, race, age, coffee and alcohol intake, consumption of cruciferous vegetables and exposure to various contaminants Tantcheva-Poor et al, 1999;Le Marchand et al, 1997), these findings have not been consistent across all studies. CYP1A2 activity has been reported to be also impaired in liver cirrhosis (Denaro et al, 1996;Bechtel et al, 2000;Lelouet et al, 2001). Conversely, a consensus in literature has identified smoking as a potent inducer of CYP1A2 activity (Campbell et al, 1987b;Rasmussen and Brosen 1996;Tantcheva-Poor et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…High CYP2A6 activity is associated with increased risk of liver and colorectal cancer (Nowell et al, 2002). Furthermore, it has been shown that CYP2A6 activity is increased in liver cirrhosis (Bechtel et al, 2000;Lelouet et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

In vivo evaluation of CYP1A2, CYP2A6, NAT‐2 and xanthine oxidase activities in a Greek population sample by the RP‐HPLC monitoring of caffeine metabolic ratios

Begas

Kouvaras

Tsakalof

et al. 2007

Biomedical Chromatography

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A RP-HPLC method was developed for the assessment of caffeine and its metabolites in urine and was used for the evaluation of the CYP1A2, CYP2A6, xanthine oxidase (XO) and N-acetyl-transferase-2 (NAT-2) in vivo activities in 44 Greek volunteers (21 men, 23 women). Spot urine samples were analyzed 6 h after 200 mg caffeine consumption, following a 30 h methylxantine-free diet. The major urinary caffeine metabolites are 1-methyluric acid (1U), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2, CYP2A6, XO and NAT-2 activities were estimated from the metabolic ratios (AFMU + 1U + 1X)/17U, 17U/17X, 1U/(1X + 1U) and AFMU/(AFMU + 1U + 1X), respectively. Metabolites and internal standard were extracted with chloroform/isopropanol (85:15, v/v) and separated on a C 18 column by an isocratic HPLC system using a two-step elution with manual switch from solvent A (0.1% acetic acid-methanol-acetonitrile, 92:4:5 v/v) to solvent B (0.1% acetic acid-methanol, 60:40, v/v), and detected at 280 nm. The method exhibited adequate metabolite separation (resolution factors >1.48), accuracy (94.1-106.3%) and intraday and interday precision <8.02 and <8.78%, respectively (n = 6). Smoking affected only CYP1A2, whereas gender had no effect in any enzyme activity. NAT-2 exhibited bimodal distribution, 63.6% of volunteers being slow acetylators. The developed RP-HPLC method was fully validated and successfully applied for the evaluation of CYP1A2, CYP2A6, XO and NAT-2 activities. Copyright

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“…Guengerich and Turvy (1991) noted similar findings in CYP1A2 immunohistochemical staining of livers with sclerosing cholangitis and cirrhosis. CYP1A2 metabolic activity has also been shown to be decreased in primary biliary cirrhosis, alcoholic steatohepatitis, and cirrhotic patients as seen by reduced clearance of known substrates antipyrine, theophylline, and caffeine (Bechtel et al, 2000;Lelouët et al, 2001;Villeneuve and Pichette, 2004). Although we report only a slight downward trend in mRNA expression of CYP1A2, the protein ( p ϭ 0.0001) and enzyme activity levels ( p ϭ 0.001) were significantly decreased with NAFLD progression.…”

Section: Fisher Et Almentioning

confidence: 99%

“…In the current study, we show that mRNA ( p ϭ 0.002), protein (0.019), and enzyme activity ( p ϭ 0.020) of CYP2A6 increased with progressive stages of NAFLD. Significantly elevated levels of CYP2A6 enzymatic activity have been reported in patients with hepatitis, primary biliary cirrhosis, and alcoholic cirrhosis (Kirby et al, 1996;Bechtel et al, 2000;Lelouët et al, 2001). In addition, induction of CYP2A5, the mouse ortholog of human CYP2A6, has been shown to be induced during oxidative injury to the endoplasmic reticulum, as well as during altered redox status (Gilmore et al, 2003;Nichols and Kirby, 2008).…”

Section: Fisher Et Almentioning

confidence: 99%

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

et al. 2009

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ABSTRACT:Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n ‫؍‬ 20; steatosis, n ‫؍‬ 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n ‫؍‬ 10; and NASH (no longer fatty), n ‫؍‬ 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p ‫؍‬ 0.001) and CYP2C19 (p ‫؍‬ 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p ‫؍‬ 0.001) and CYP2C9 (diclofenac, p ‫؍‬ 0.0001; tolbutamide, p ‫؍‬ 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor ␣ and interleukin 1␤ was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1␣ expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.

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Caffeine metabolism in a group of 67 patients with primary biliary cirrhosis

Cited by 17 publications

References 0 publications

CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives

CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives

In vivo evaluation of CYP1A2, CYP2A6, NAT‐2 and xanthine oxidase activities in a Greek population sample by the RP‐HPLC monitoring of caffeine metabolic ratios

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

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