Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites

Clomiphene citrate is the most used drug for the treatment of female infertility, a common condition in western societies and developing countries. Despite dose escalation, up to 30% of women do not respond. Since clomiphene shares structural similarities with tamoxifen, which is predominantly bioac...

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Vydáno v:Human molecular genetics Ročník 21; číslo 5; s. 1145
Hlavní autoři: Mürdter, Thomas E, Kerb, Reinhold, Turpeinen, Miia, Schroth, Werner, Ganchev, Boian, Böhmer, Gabriele M, Igel, Svitlana, Schaeffeler, Elke, Zanger, Ulrich, Brauch, Hiltrud, Schwab, Matthias
Médium: Journal Article
Jazyk:angličtina
Vydáno: England 01.03.2012
Témata:
Biotransformation
Clomiphene - analogs & derivatives
Clomiphene - chemistry
Clomiphene - metabolism
Clomiphene - pharmacology
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 - metabolism
Estrogen Antagonists - metabolism
Estrogen Antagonists - pharmacology
Female
Genotype
Humans
Microsomes, Liver - metabolism
Molecular Structure
Polymorphism, Genetic
Receptors, Estrogen - antagonists & inhibitors
Receptors, Estrogen - metabolism
Recombinant Proteins - metabolism
ISSN:1460-2083, 1460-2083
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Popis
Shrnutí:Clomiphene citrate is the most used drug for the treatment of female infertility, a common condition in western societies and developing countries. Despite dose escalation, up to 30% of women do not respond. Since clomiphene shares structural similarities with tamoxifen, which is predominantly bioactivated by the polymorphic cytochrome P450 (CYP) 2D6, we systematically explored clomiphene metabolism and action in vitro and in vivo by pharmacogenetic, -kinetic and -dynamic investigations. Human liver microsomes were incubated with clomiphene citrate and nine metabolites were identified by mass spectrometry and tested at the oestrogen receptor for their antagonistic capacity. (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed strongest inhibition of the oestrogen receptor activity with 50% inhibitory concentrations of 2.5 and 1.4 nm, respectively. CYP2D6 has been identified as the major enzyme involved in their formation using recombinant CYP450 isozymes as confirmed by inhibition experiments with CYP monoclonal antibodies. We correlated the CYP2D6 genotype of 30 human liver donors with the microsomal formation rate of active metabolites and observed a strong gene-dose effect. A healthy female volunteer study confirmed our in vitro data that the CYP2D6 polymorphism substantially determines the formation of the active clomiphene metabolites. Comparison of the C(max) of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed 8 and 12 times lower concentrations in subjects with non-functional CYP2D6 alleles. Our results highlight (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene as the active clomiphene metabolites, the formation of which strongly depends on the polymorphic CYP2D6 enzyme. Our data provide first evidence of a biological rationale for the variability in the response to clomiphene treatment.
Bibliografie:ObjectType-Article-1
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ISSN:1460-2083
1460-2083
DOI:10.1093/hmg/ddr543