Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xenobiotics have played a role in elucidating the regulation of gene expression of hepatic cytochrome P450 in the eukaryotes. The major regulation of P450 genes in the eukaryotes is at the transcriptional and post transcriptional level. Polycyclic aromatic hydrocarbons regulate the gene expression by binding the cytosolic aryl hydrocarbon receptor and its translocation to the nucleus where it forms a ternary complex with aryl hydrocarbon nuclear translocator. The ternary complex PAH-AHR-ARNT acts as a transcription factor and binds aromatic hydrocarbon responsive element to increase the expression of CYP1A1 gene. Phenobarbitone and ethanol regulate the expression of respective P450s within CYP2 gene family by different mechanisms but without the involvement of a cytosolic receptor. PB uses phosphorylation as a switch to increase the affinity of the transcription factor(s) for the positive rather than negative PB regulatory element within CYP2B1/2. This is one of the novel ways that nature has designed for a protein to act as a negative as well as a positive acting transcription factor. Ethanol regulates the expression of CYP2E1 by posttranslational stabilization making it resistant to the proteolytic digestion. Steroids regulate expression of CYP3A genes through a receptor mediated mechanism. The binary complex of the steroid and its receptor increases the transcription of CYP3 genes by binding glucocorticoid responsive element which is already occupied by another protein. Peroxisome proliferators also follow a receptor mediated mechanism in which a binary complex of PP activated receptor and retinoid X receptor acts a transcription factor and increases the expression of CYP4A genes by binding peroxisome proliferator responsive element. These studies demonstrate that PAH, glucocorticoids and PP follow a receptor mediated whereas PB and ethanol follow a nonreceptor mediated mechanism for the regulation of respective P450 genes in the eukaryotes.
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PMID:Gene regulation of cytochrome P450--an overview. 971 60

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.
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PMID:Permissive and suppressive effects of dexamethasone on enzyme induction in hepatocyte co-cultures. 1229 87