title: Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol.
abstract: OBJECTIVE
  Brain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ-specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone.
  
  
  METHODS
  The regulation of CYP2D and brain-enriched miRNAs by testosterone was investigated using SH-SY5Y cells, U251 cells, and HepG2 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.
  
  
  RESULTS
  miR-101 and miR-128-2 bound the 3'-untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up-regulation of miR-101 and miR-128-2 in SH-SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR-101 and miR-128-2 in the hippocampus of male GHR-KO mice, indicating that androgens regulate miRNAs 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 CYP2D inhibitor.
  
  
  CONCLUSIONS
  The selective regulation of brain CYP2D via brain-enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances.
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Baotou Teachers' College, Inner Mongolia University of Science and Technology, Baotou, China.
authors.forename: Guicheng
authors.initials: G
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009919:Orchiectomy; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013739:Testosterone / Q000494:pharmacology*; D014147:Tramadol / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000728:Androgens; D035683:MicroRNAs; D012333:RNA, Messenger; D014147:Tramadol; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol