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

Sinués, B.; Fanlo, Ana; Mayayo, E; Carcas, Cristina; Vicente, Jorge; Arenaz, Izaskún; Cebollada, Alberto

doi:10.1177/0960327107082224

Cited by 29 publications

(24 citation statements)

References 38 publications

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“…So far, higher enzyme activity in women compared to men was observed in European-Americans, 9,18,23) Africans, 20,31) Spanish, 18,21) British, 12) and Thais. 6) Some of the previous studies also reported increased enzyme activity in OC users, 21,23) suggesting estrogen as the mechanism of CYP2A6 induction in women. 23) Yet, the findings on association between CYP2A6 and sex were not always consistent, as no significant sex differences in enzyme activity was discovered in Chinese, 42) Greeks, 26) Serbs, 22) or Caucasians in general.…”

Section: Discussionmentioning

confidence: 96%

“…CYP2A6 enzyme activity can be determined by several phenotyping strategies, including coumarin, 6,25) nicotine, 13,31) cotinine, 38) and caffeine 21,22) methods. In the present study, we used caffeine as a probe drug, and estimated enzyme activity using the urine 17X/ 17U ratio as an index.…”

Section: Discussionmentioning

confidence: 99%

“…1,7) Due to potential clinical importance, this pronounced variation and its possible causes have been widely investigated. Numerous factors affecting CYP2A6 enzyme activity have been described, including ethnicity, 18) genotype, 9,19) sex, 18,20) age, 12,21) cigarette smoking 20,22) and oral contraceptive (OC) use. 21,23) However, the findings were not always consistent, 22,[24][25][26] warranting further investigations.…”

Section: Introductionmentioning

confidence: 99%

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Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans

Djordjević

Carrillo

Broek

et al. 2013

Drug Metabolism and Pharmacokinetics

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The aim was to compare cytochrome P450 2A6 (CYP2A6) genotype and enzyme activity between Swedes and Koreans, and to investigate the influence of genotype, sex, age, cigarette smoking and oral contraceptive (OC) use on enzyme activity. The study involved 190 Swedes and 144 Koreans. Genotyping for CYP2A6*1B, *1×2, *4, *5, *7, *8, *9, *10, *18 and *19 alleles was done. Using caffeine as a probe, in vivo CYP2A6 activity was estimated by the 17U/17X urinary ratio. Multiple regression analysis indicated ethnicity (p=0.0001) and CYP2A6 genotype (p=0.006), but not sex, age, cigarette smoking or OC use as predictors of CYP2A6 activity. There were significant differences in CYP2A6 genotype distribution and enzyme activity between Swedes and Koreans. Functional CYP2A6 alleles and rapid genotypes were more frequent in Swedes, whereas the defective alleles and slow genotypes were more frequent in Koreans (p≤0.0001). Distribution of log 17U/17X was bimodal in Koreans but unimodal in Swedes with a common antimode at 0.01, classifying 3.16% of Swedes and 18.75% of Koreans as slow metabolizers. CYP2A6 activity was higher in Swedes compared to Koreans (p<0.0001), even among carriers of rapid genotypes. We report major differences in CYP2A6 enzyme activity between Swedes and Koreans mainly due to CYP2A6 genetic variation but not exclusively.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans

Djordjević

Carrillo

Broek

et al. 2013

Drug Metabolism and Pharmacokinetics

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“…There is also evidence for higher CYP2A6 activity in women (Sinues et al, 2008), although that could, in part, reflect the use of estrogen-containing contraceptives, given the estrogen responsiveness of the human CYP2A6 gene (Higashi et al, 2007). CYP1A2 substrates, including caffeine and the antipsychotic agents olanzapine and clozapine, show higher clearance rates in men (Schwartz, 2007).…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

634

584

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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“…Moreover, CYP2A6 enzyme activity appears to be affected by concomitant drug use, including rifampicin, dexamethasone, phenobarbital, and ketokonazole Tomaszewski et al, 2008) CYP2A6 enzyme activity display pronounced inter-ethnic variations between African Americans, Asians, and Caucasians (Djordjevic et al, 2010;Kandel et al, 2007;Nakajima et al, 2006), and CYP2A6 genetic variation is commonly considered as the major cause for the observed differences. Various factors such as ethnicity (Djordjevic et al, 2010(Djordjevic et al, , 2013Kandel et al, 2007;Nakajima et al, 2006), genotype Pitarque et al, 2004), sex (Kandel et al, 2007;Mwenifumbo et al, 2007), age ( Johnstone et al, 2006;Sinues et al, 2008), cigarette smoking (Djordjevic et al, 2010;Mwenifumbo et al, 2007), and oral contraceptive use (Sinues et al, 2008) are reported to influence CYP2A6 enzyme activity. However, such findings are often inconsistent (Begas et al, 2007;Djordjevic et al, 2010;Kadlubar et al, 2009;Mahavorasirikul et al, 2009), warranting further investigations.…”

Section: Introductionmentioning

confidence: 99%

High CYP2A6 Enzyme Activity as Measured by a Caffeine Test and Unique Distribution of CYP2A6 Variant Alleles in Ethiopian Population

Aklillu

Djordjević

Carrillo

et al. 2014

OMICS: A Journal of Integrative Biology

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CYP2A6 metabolizes clinically relevant drugs, including antiretroviral and antimalarial drugs of major public health importance for the African populations. CYP2A6 genotype-phenotype relationship in African populations, and implications of geographic differences on enzyme activity, remain to be investigated. We evaluated the influence of CYP2A6 genotype, geographical differences, gender, and cigarette smoking on enzyme activity, using caffeine as a probe in 100 healthy unrelated Ethiopians living in Ethiopia, and 72 living in Sweden. CYP2A6 phenotype was estimated by urinary 1,7-dimethyluric acid (17U)/1,7-dimethylxanthine or paraxanthine (17X) ratio. The frequencies of CYP2A6*1B, *1D, *2, *4, *9, and *1x2 in Ethiopians were 31.3, 29.4, 0.6, 0.6, 2.8, and 0.3%, respectively. The overall mean -SD for log 17U/17X was 0.12 -0.24 and coefficient of variation 199%. No significant difference in the mean log 17U/17X ratio between Ethiopians living in Sweden versus Ethiopia was observed. Analysis of variance revealed CYP2A6 genotype ( p = 0.04, F = 2.01) but not geographical differences, sex, or cigarette smoking as predictors of CYP2A6 activity. Importantly, the median (interquartile range) of 17U/17X ratio in Ethiopians 1.35 (0.99 to 1.84) was 3-and 11-fold higher than the previously reported value in Swedes 0.52 (0.27 to 1.00) and Koreans 0.13 (0.0 to 0.35), respectively (Djordjevic et al., 2013). Taken together, we report here the relevance of CYP2A6 genotype for enzyme activity in this Ethiopian sample, as well as high CYP2A6 activity and unique distribution of the CYP2A6 variant alleles in Ethiopians as compared other populations described hitherto. Because Omics biomarker research is rapidly accelerating in Africa, CYP2A6 pharmacogenetics and clinical pharmacology observations reported herein for the Ethiopian populations have clinical and biological importance to plan for future rational therapeutics efforts in the African continent as well as therapeutics as a global science.

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

Cited by 29 publications

References 38 publications

Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans

Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

High CYP2A6 Enzyme Activity as Measured by a Caffeine Test and Unique Distribution of CYP2A6 Variant Alleles in Ethiopian Population

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