Although it is believed that CYP
Although it is believed that CYP induction is regulated in humans in principle in the same fashion as in animals, some species differences in CYP3A enzymes induction were observed. Rifampicin is known to be a potent inducer of CYP3A4 in human hepatocytes, whereas pregnenolone-16α-carbonitrile (PCN) has little effect. In contrast, PCN is a potent inducer of rat CYP3A forms, whereas rifampicin has little effect . The induction of main human lung CYP3A, CYP3A5 and rat CYP3A1/CYP3A23 genes with a physiological concentration of glucocorticoids proceeds via the classic GR pathway [10, 11, 22]. The CYP3A2 gene responds to a lesser extent to treatment with dex-amethasone than does CYP3A1/CYP3A23 . PXR and CAR are activated by xenobiotics and high concentrations of glucocorticoids (PXR). Dexamethasone is a potent inducer of CYP3A in rat hepatocytes, whereas it is a weak inducer of CYP3A in human hepatocytes, which may be due to differences in the sensitivity (ligand affinity) and/or specificity for these nuclear receptors between primates and rodents . It has been shown that synthetic steroids (e.g., dex-amethasone) are more efficacious activators of PXR in rodents than in humans . Subsequently, the structural differences in PXR were identified as the cellular factor responsible for species differences in CYP3A induction .
In summary, it seems that the direct inhibitory effect of the investigated neuroleptics with Ki values below 100μM found in vitro (thioridazine, chlorpromazine), as well as indirect effects produced by one-day treatment with chlorpromazine or two-week treatment with thioridazine and risperidone may be of physiological, pharmacological or toxicological importance in vivo. Moreover, considering some similarities in the regulation of CYP3A isoforms, homology of the amino 2478 sequence and functional analogy between the rat and human CYP3A, the pharmacokinetics interactions with CYP3A4-catalyzed metabolism (steroids, drugs or procarcinogens) may be expected in patients treated with neuroleptics.
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Introduction Triptolide (TP) is derived from the root extract of the traditional Chinese herb, Tripterygium wilfordii Hook. F. (TWHF) (lei gong teng). It is a purified diterpenoid triepoxide compound and has been used for centuries to treat autoimmune and inflammatory diseases, as well as cancers. TP is effective in the treatment of rheumatoid arthritis, immune complex nephritis, systemic lupus erythematosus (SLE) and also used in organ and tissue transplantation (Chen, 2001, Yang et al., 2003, Panichakul et al., 2006). Although TP is used to treat a variety of diseases, it is extremely toxic to both humans and animals and may cause damage to liver, intestine, nerves, and other systems in the body. Recently, hepatotoxicity induced by TP in animals and humans was reported by many researchers (He et al., 2006, Mei et al., 2005, Wang et al., 2007, Yao et al., 2008). For example, Liu et al. (2010) found that potential hepatotoxicity in rats treated with TP for 28days was associated with increased levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (Liu et al., 2010). Moreover, it was also reported that oral administration of TP in rats could lead to liver injury or even death (Fu et al., 2011). Drug-induced toxicity is caused either by parent compounds or by their reactive metabolites that are generated through biotransformation primarily in the liver (Srivastava et al., 2010). The cytochrome P450 (CYP) superfamily members contribute to approximately 80% of this process (Evans and Relling, 1999). Previous work has indicated that CYP enzymes mediated TP metabolism could have an impact on its toxicity (Li et al., 2008). In vitro studies demonstrated that two isoenzymes, CYP3A4 and CYP2C19, were involved in the conversion of TP into its mono-hydroxylated metabolites (Li et al., 2008). Further investigation showed that high active hepatic CYP3A levels induced by dexamethasone treatment significantly increased the level of the mono-hydroxylated metabolite of TP and decreased its hepatotoxicity in rats (Ye et al., 2010). In vivo studies demonstrated that inactivation of hepatic CYP enzymes abolished the metabolism of TP in the liver, which subsequently resulted in an increase in bioavailability and toxicity of TP in rats (Xue et al., 2011). It is well accepted that among the three major mechanisms for CYP involvement in drug–drug interactions, induction, inhibition and possibly stimulation, inhibition appears to be the most important in terms of known clinical problems (Guengerich, 1997). Therefore, investigations on the effects of CYP inhibition or inactivation in TP-induced toxicity, which to date remain unclear, could provide important information for the safe use of TP in the clinic.