ABSTRACT
In our preliminary studies, we observed zolmitriptan (ZOL) treatment led to induction of CYP3A2 in male not female rats. To figure out the reason is of great significance for drug-drug interactions and personalized administration. Since growth hormone (GH) is known as the major mechanistic determinant of sexually-dimorphic gene expression like CYP3A2 in rat liver, the impacts of ZOL on both plasma GH levels in non monosodium glutamate (MSG)-treated rats and CYP3A2 expression in GH depleted MSG-treated rats were studied. ZOL was shown to partially suppress GH levels in both genders. Furthermore, CYP3A2 protein and mRNA level declined in male not female MSG-treated rats. In order to study the possible molecular events involved in the depression of GH and gender-selective induction on rat CYP3A2 by ZOL, the mRNA and protein level (whole protein and nuclear protein) of hepatocyte nuclear factor 4α (HNF4α) was investigated. Nuclear accumulation of HNF4α was observed in the normal male not female rat liver tissue following ZOL treatment. However, this kind of nuclear translocation did not occur in rat hepatocytes and MSG-treated rats. These findings demonstrated CYP3A2 inducibility by ZOL was gender-selective. GH and HNF4α may play an important role in CYP3A2 induction.
ABSTRACT
OBJECTIVE: To investigate the effects of episodic hypoxia(EHYP) on liver CYP3A2 and CYP2E1. METHODS: Healthy masculinity rats were divided randomly into five groups: control group, 3 -day EHYP group, 7 -day EHYP group, 14 -day EHYP group, and 28 -day EHYP group. 24 h after the management of EHYP, the rats were anesthetized by intraperitoneal injection, and the eyeball blood 2ml was drawn to prepare serum. The activities of ALT and AST in the serum were determined by enzymatic methods. The activities of liver microsomal erythromycin demethylase(ERD) and aniline hydroxylase(ANH) were detected by spectrophotography. The levels of mRNA expression of CYP3A2,CYP2E1 were assayed with RT-PCR. RESULTS: The serum activities of ALT,AST showed no remarkable change. However, after 7 days of hypoxia, ERD and ANH activities were remarkably elevated, and at 28 days induction rates reached up to155.5% and 42.2%, respectively. Meanwhile, the levels of mRNA expression of CYP3A2,CYP2E1 also increased by 220.5% and 102.8%, respectively. CONCLUSION: Chronic EHYP can remarkably increase the activities of ERD and ANH, whose mechanism is probably related to up-regulating of CYP3A2 and CYP2E1 expression at the transcriptive level.