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  • It is particularly notable that CYP


    It is particularly notable that CYP2D6 appears to be the most stable of the major CYP450 fgfr inhibitor in its expression over time in vitro and appears to be least affected by culture conditions and sample to sample variability (i.e., CYP2D6 expression is remarkably consistent over time and between individual cell preparations) (Coon et al., 1999). These results, in conjunction with the fact that CYP2D6 is not inducible, suggest that CYP2D6 could represent a possible ‘internal standard’ by which to normalize in vitro data or by which to normalize drug-induced changes in other CYP450 enzyme expression levels (albeit polymorphisms exist in <10% of the Caucasian population). The utility of CYP2D6 expression as a marker activity in vitro warrants further investigation.
    Inter-preparation variability in cytochrome P450 induction Preparation-to-preparation variability in the extent of induction of various cytochrome P450 enzymes is fairly extensive in primary cultures of human hepatocytes. Fig. 9 illustrates some of the variability in CYP1A2, CYP2C9 and CYP3A4 inducibility, as represented by 7-ethoxyresorufin O-dealkylase, tolbutamide methylhydroxylase and testosterone 6β-hydroxylase activities, respectively, in microsomes prepared from multiple cultures of human hepatocytes treated with β-naphthoflavone or rifampin. Although there is considerable sample-to-sample variation (∼3-fold) in the ‘induced’ values of microsomal CYP activities, there is even greater variation in the corresponding ‘control’ activities (8–10-fold). Notably, the variability in the control activities observed for CYP1A2, CYP2C9 and CYP3A4 in individual preparations of hepatocytes does not correlate with the absolute values of the corresponding activities in induced cultures. When evaluated for sex-related differences, no significant differences are observed between either the basal or RIF-induced levels of CYP3A4 activity in hepatocytes from males versus females (Fig. 9G). Overall, these results indicate that there may be greater individual differences in the basal expression of CYP3A4 that is independent of any exogenous stimuli and that there is an inherent biochemical limit to the degree to which hepatocytes can be induced (i.e., synthesize active CYP450 enzyme). In addition, it appears that there is a threshold or ‘ceiling’ above which an individual cannot be induced and, thus, the fold induction elicited by a particular drug is primarily dependent on the basal level of expression within that individual. Therefore, one would predict that there should be an inverse correlation between the control levels of CYP3A4 catalytic activity and the fold induction observed after treatment with an inducer. Notably, this has been observed both in vivo and in vitro in studies examining the induction potential of dexamethasone, taxol, and rifampicin (Kostrubsky et al., 1999, McCune et al., 2000).
    Nuclear receptor activation and CYP450 regulation in human hepatocytes
    Current recommendations and future considerations
    In vitro screening for enzyme induction: an overview The techniques currently available for measuring enzyme induction (in a manner that permits the identification of which particular enzymes are induced) fall into two categories: ex vivo and in vitro (Parkinson, 1996a, Parkinson, 1996b, Maurel, 1996a). The ex vivo technique is particularly applicable to studies in laboratory animals, where a drug is administered in vivo and, after a certain time (typically several days to several weeks), the liver is removed and analyzed for increased expression of certain CYP450 enzymes. This technique is still considered by most to be the most reliable strategy for assessing the enzyme-inducing potential of drugs and other xenobiotics, and it can also be used to detect the ability of certain NCEs, such as cytokines and pro-inflammatory agents, to suppress the expression of cytochrome P450. However, the ex vivo approach cannot be applied to humans, for obvious ethical reasons, and there is reason to doubt the relevance of induction in animals to humans. For this reason, the development of an in vitro system based on human hepatocytes that might be used to assess the capacity of drugs and NCEs to induce (or possibly suppress) human CYP450 enzymes under clinically relevant conditions is still a very appropriate and worthwhile endeavor (Donato et al., 1995, Maurel, 1996a, Li et al., 1997a, Silva et al., 1998, LeCluyse et al., 2000a).