Inhibition of human liver steroid sulfotransferase activities by drugs: a novel mechanism of drug toxicity?
The inhibition of steroid and phenol sulfotransferase activities in human liver cytosol by a wide range of commonly used drugs was studied. Dehydroepiandrosterone (DHEA) and estrone sulfotransferase activities were strongly inhibited by a number of compounds, with IC50 values ranging between 440 pM and 147 microM. For DHEA sulfotransferase, clomiphene, testosterone, danazol and spironolactone were the best inhibitors, with IC50 values less than 5 microM, whereas for estrone sulfotransferase cyclizine, ibuprofen, chlorpheniramine and dimenhydrinate resulted in the strongest inhibition, again with IC50 values of less than 5 microM. The xenobiotic substrate 1-naphthol was refractory to substantial inhibition, with the exception of clomiphene. The majority of the drugs which inhibited steroid ST activities strongly were either synthetic steroids, antisteroidals or were tertiary amine drugs such as tricyclic antidepressants and antihistamines, many of which exhibit adverse side effects manifesting particularly as sexual dysfunction and disruption of hormone action in clinical use. The importance of these findings for our understanding of the molecular basis of adverse drug reactions is discussed.
Bamforth
K J
KJ
Department of Biochemical Medicine, University of Dundee, Ninewells Hospital and Medical School, Scotland, UK.
Dalgliesh
K
K
Coughtrie
M W
MW
D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003687:Dehydroepiandrosterone / Q000037:antagonists & inhibitors*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D015238:Sulfotransferases; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors*
D003687:Dehydroepiandrosterone; D013466:Sulfurtransferases; D015238:Sulfotransferases; C020122:estrone sulfotransferase