Permissive and suppressive effects of dexamethasone on enzyme induction in hepatocyte co-cultures

Abstract

1. Steroids are known to act as permissive factors in hepatocytes. This study shows that dexamethasone (DEX) is a permissive factor for induction of CYP2B1/2, CYP3A1, CYP2A1 and probably also CYP2C11 in cultures with primary rat hepatocytes. 2. The induction factor of phenobarbital (PB)-induced formation of 16beta-hydroxytestosterone (OHT), a testosterone biotransformation product predominantly formed by CYP2B1, is increased 18-fold by the addition of 32 nM DEX to the culture medium. Interestingly, higher concentrations of DEX up to 1000 nM led to a concentration-dependent maximally 5-fold decrease (p = 0.002) of phenobarbital-induced 16beta-OHT formation compared with the effect observed with 32 nM DEX. Thus, DEX shows permissive and suppressive effects on enzyme induction depending on the concentration of the glucocorticoid. 3. Qualitatively similar but smaller permissive and suppressive effects of DEX were observed for PB-induced CYP3A1 activity as evidenced by formation of 2beta-, 6beta- and 15beta-OHT. 4. DEX is a permissive factor for induction of CYP2A1 activity by 3-methylcholanthrene (3MC), as evidenced by the formation of 7alpha-OHT. Without addition of DEX, 3MC did not induce formation of 7alpha-OHT, whereas an almost 3-fold induction occurred in the presence of DEX. In contrast to CYP2B and CYP3A, concentrations up to 1000 nM DEX were not suppressive for the induction of CYP2A1. 5. We described recently a technique that allows preparation of cultures from cryopreserved hepatocytes. An almost identical influence of dexamethasone on enzyme induction was observed here in cultures from cryopreserved compared with freshly isolated hepatocytes. 6. Cultures with primary hepatocyte cultures represent a well-established technique for the study of drug-drug interactions. However, a large interlaboratory variation is known. Our study provides evidence that differences in glucocorticoid concentration in the culture medium contribute to this variation.

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

“…In rat hepatocytes, it was shown that addition of DEX (100 nM) to the medium increased the inducibility of CYP2B (Ringel et al, 2002). In the present study in colon but not in small intestinal slices, DEX appeared to enormously induce CYP2B15 mRNA.…”

Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro

“…This result could be due to the relatively short incubation time chosen in our studies (24 h). Induction of DMEs has been shown to be dependent on the concentration of the inducer and incubation period (Jigorel et al, 2006), on the presence of supplements in the incubation medium (Ringel et al, 2002), and also on the type of cell line used (Hartley et al, 2006). Therefore, "falsenegative" results could be explained by these factors.…”

Illegal Drug Treatments and Drug Metabolism: Biomarkers or Not?

“…Nevertheless, it is well known that some specific situations (i.e., stress, immunological response, pathologic conditions) can modulate the expression of CYP3A. Moreover, DEX has been demonstrated to have either a permissive or a repressive effect on several CYP isoforms, sometimes depending on the dose used (Iber et al, 1997;Ringel et al, 2002). CYP3A expression was never affected by the treatment in the other experiments cited above and executed in poultry and meat cattle (Nebbia et al, 1996;Cantiello et al, 2002;Capolongo et al, 2004;Merlanti et al, unpublished;Dacasto et al, unpublished).…”