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Sex hormones regulate cerebral drug metabolism via brain miRNAs: down‐regulation of brain CYP 2 D by androgens reduces the analgesic effects of tramadol
Author(s) -
Li Jie,
Xie Mengmeng,
Wang Xiaoshuang,
Ouyang Xiufang,
Wan Yu,
Dong Guicheng,
Yang Zheqiong,
Yang Jing,
Yue Jiang
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13206
Subject(s) - medicine , endocrinology , testosterone (patch) , microdialysis , orchiectomy , androgen , chemistry , androgen deprivation therapy , hormone , pharmacology , biology , dopamine , prostate cancer , cancer
Background and Purpose Brain cytochrome P450 2D ( CYP 2 D ) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP 2 D can be regulated in an organ‐specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNA s in the selective regulation of brain CYP 2 D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone. Experimental Approach The regulation of CYP 2 D and brain‐enriched miRNA s by testosterone was investigated using SH ‐ SY 5 Y cells, U 251 cells, and H ep G 2 cells as well as orchiectomized growth hormone receptor knockout ( GHR‐KO ) mice and rats. Concentration–time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail‐flick test in rats. Key Results miR ‐101 and miR ‐128‐2 bound the 3′‐untranslated region of the CYP 2 D 6 mRNA and decreased its level. Testosterone decreased CYP 2 D 6 catalytic function via the up‐regulation of miR ‐101 and miR ‐128‐2 in SH ‐ SY 5 Y and U 251 cells, but not in H ep G 2 cells. Orchiectomy decreased the levels of miR ‐101 and miR ‐128‐2 in the hippocampus of male GHR‐KO mice, indicating that androgens regulate miRNA s directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP 2 D inhibitor. Conclusions and Implications The selective regulation of brain CYP 2 D via brain‐enriched miRNA s, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances.