Sexually dimorphic testosterone hydroxylase activities have

Sexually dimorphic testosterone hydroxylase activities have been suggested as a biomarker of endocrine disruption caused by xenobiotics (Wilson et al., 1999). The results from the studies reported here suggest that dietary exposure to the endocrine active test compounds, all of which have demonstrated estrogenic activity, during development can result in alterations in testosterone hydroxylase and 5α-reductase activities, CYP450 and ERα expression in the liver, particularly in male rats, but that these changes cannot be directly linked to their estrogenic activities. Thus, these assays are not appropriate as biomarkers for exposure to estrogenic agents. The implications of the observed changes for the biological activity of the compounds is unclear. Several studies have suggested the potential contributing role of alterations in steroid metabolism JNK-IN-7 in the toxicity of endocrine active compounds (LeBlanc, Bain, & Wilson, 1997, You et al., 1999). Data from recent experiments in our laboratory with both nonylphenol (E. M. Laurenzana et al., unpublished) and genistein (A. Dalu et al., unpublished data) indicate that serum testosterone concentrations are not altered significantly in pubertal animals under the exposure conditions described here, suggesting that the magnitude of the observed enzyme changes are not sufficient to alter testosterone homeostasis. Other rat colonies or strains could respond differently to the treatments for a variety of reasons (e.g. metabolism of the test compound). We did not measure absolute levels of the CYP450 enzymes or estrogen receptors in our animals, but it is expected that there would be a large degree of variability in expression of these proteins and in their response to xenobiotic agents in different rodent populations. The question of whether the changes in hepatic CYP450 and ERα under the exposure conditions used in the present experiment reflect alterations of the hypothalamic–pituitary–gonadal axis that portend more serious long-term consequences will be determined in the ongoing multigeneration and chronic toxicity studies being conducted with these agents.
Acknowledgements
Introduction Following the approval of first tyrosine kinase inhibitor (TKI), imatinib, in 2001 by the US Food and Drug Administration (FDA), several TKIs have entered the market. Currently, TKIs are receiving considerable attention in cancer treatment owing to their excellent efficacy and low toxicity compared to those of traditional chemotherapeutic agents [1]. However, a major problem associated with TKI treatment is frequent clinical drug-drug interactions (DDIs) [[2], [3], [4], [5], [6], [7]]. Dasatinib (Sprycel®) and nilotinib (Tasignais®) are orally administered TKIs used for the treatment of chronic myeloid leukemia (CML) [2,5,8]. Both drugs extensively undergo cytochrome P4503A4 (CYP3A4)-mediated biotransformation, with the involvement of other enzymes to a lesser extent. In vitro studies have demonstrated their mechanism-based CYP3A4 inhibition [5,9]. Few studies have reported that dasatinib and nilotinib can increase the exposure of CYP3A4 substrates simvastatin and midazolam, respectively, in humans [2,4,5]. However, there is a lack of detailed information on the effect of dasatinib on other CYP3A4 substrates. While some research has been performed to determine the benefit of dasatinib and cyclosporine combination therapy [10,11], considering the chronic prescription patterns for TKIs, the current study was undertaken to fill the gaps in literature with regard to the effects of dasatinib and nilotinib on cyclosporine pharmacokinetics.