Variation in coumarin 7-hydroxylase activity associated with genetic polymorphism of cytochrome P450 2A6 and the body status of iron stores in adult Thai males and females

Abstract

The relationships between catalytic activity of cytochrome P450 2A6 (CYP2A6), polymorphism of CYP2A6 gene, gender and levels of body iron stores were analysed in a sample group of 202 apparently healthy Thais, aged 19-47 years. Eleven individuals were found to have high activity of CYP2A6, judged by the relatively large amounts (11.2-14.6 mg) of 7-hydroyxcoumarin (7-OHC) excreted 3 h following administration of 15 mg of coumarin. Ten individuals, however, did not excrete any 7-OHC. Of these 10, four were found to have no CYP2A6 gene (whole gene deletion; CYP2A6*4 allele). The frequency of the CYP2A6 alleles; *1A, *1B and *4 in the whole sample group was 52, 40 and 8% while the frequency of the CYP2A6 gene types; *1A/*1A, *1A/*1B, *1B/*1B, *1A/*4, *1B/*4, *4/*4 was 29, 41, 16, 7, 5 and 2%. Subjects having CYP2A6*1A/*1B gene-type group were found to have higher rates of coumarin 7-hydroxylation compared with those of the CYP2A6*1B/*1B and CYP2A6*1A/*4 gene types. The inter-individual variability in CYP2A6 catalytic activity was therefore attributed in part to the CYP2A6 genetic polymorphism. Variation in CYP2A6 activity in this sample group was not associated with gender but, interestingly, it did show an inverse association with plasma ferritin; an indicator of body iron stores. Higher rates of coumarin 7-hydroxylation were found in individuals with low body iron stores (plasma ferritin < 20 microg/l) compared with subjects having normal body iron store status. Subjects (n = 16) with iron overload (plasma ferritin > 300 microg/l) also tended to have elevated rates of coumarin 7-hydroxylation. These results suggest an increased CYP2A6 expression in subjects who have excessive body iron stores. Further investigations into the underlying factors that may lead to increased expression of CYP2A6 in association with abnormal body iron stores are currently in progress in our laboratory.

Metabolism and Disposition Kinetics of Nicotine

“…Two of these studies showed a statistically significant 98 difference; 17% higher 3-h urinary excretion of 7-hydroxycoumarin in females compared with males was reported by Ujjin et al (2002), and the study by Iscan et al (1994) showed 11% higher 7-hydroxycoumarin excretion in women compared with men in a 2-h coumarin test. A third study showed significantly higher activity in women compared with men only in a subpopulation with lower coumarin hydroxylase activity (Xu et al, 2002c).…”

“…A tendency for higher metabolism in women compared with men has been detected in most (six of seven studies) of the phenotyping studies using coumarin 7-hydroxylation or conversion of caffeine metabolite 1,7-dimethylxanthine to 1,7-dimethyluric acid as a measure of CYP2A6 activity (Rautio et al, 1992;Iscan et al, 1994;Sotaniemi et al, 1996;Krul and Hageman, 1998;Nowell et al, 2002;Ujjin et al, 2002;Xu et al, 2002c). Two of these studies showed a statistically significant 98 difference; 17% higher 3-h urinary excretion of 7-hydroxycoumarin in females compared with males was reported by Ujjin et al (2002), and the study by Iscan et al (1994) showed 11% higher 7-hydroxycoumarin excretion in women compared with men in a 2-h coumarin test.…”

Human CYP2A6 Is Induced by Estrogen via Estrogen Receptor

“…First, sex differences in CYP2A6 activity have been reported. For example, the urinary excretion level of 7-hydroxycoumarin formed from coumarin by CYP2A6 was significantly higher in women than in men (Iscan et al, 1994;Ujjin et al, 2002). The ratio of cotinine/nicotine in plasma was higher in women than in men (Nakajima et al, 2006a).…”

Dexamethasone-Mediated Up-Regulation of HumanCYP2A6Involves the Glucocorticoid Receptor and Increased Binding of Hepatic Nuclear Factor 4α to the Proximal Promoter

“…Twenty-six allelic variants of CYP2A6 have been identified to date, resulting in altered enzyme activity that affects the metabolism of substrates ranging from pharmaceuticals to toxins including procarcinogens (Raunio et al, 2001). Although interindividual variation in CYP2A6 levels has been attributed to physiological factors (Ujjin et al, 2002), inflammatory disease (Kirby et al, 1996), pharmaceutical exposure (Sotaniemi et al, 1995;Pelkonen et al, 2000), and genetic polymorphisms within the CYP2A6 coding region (Raunio et al, 2001), little is known about CYP2A6 transcriptional regulation and its involvement in the observed variation in expression.…”