Nuclear receptor-mediated transcriptional regulation in Phase I, II, and III xenobiotic metabolizing systems.
Studies of the genetic regulation involved in drug metabolizing enzymes and drug transporters are of great interest to understand the molecular mechanisms of drug response and toxic events. Recent reports have revealed that hydrophobic ligands and several nuclear receptors are involved in the induction or down-regulation of various enzymes and transporters involved in Phase I, II, and III xenobiotic metabolizing systems. Nuclear receptors (NRs) form a family of ligand-activated transcription factors (TFs). These proteins modulate the regulation of target genes by contacting their promoter or enhancer sequences at specific recognition sites. These target genes include metabolizing enzymes such as cytochrome P450s (CYPs), transporters, and NRs. Thus it was now recognized that these NRs play essential role in sensing processing xenobiotic substances including drugs, environmental chemical pollutants and nutritional ingredients. From literature, we picked up target genes of each NR in xenobiotic response systems. Possible cross-talk, by which xenobiotics may exert undesirable effects, was listed. For example, the role of NRs was comprehensively drawn up in cholesterol and bile acid homeostasis in human hepatocyte. Summarizing current states of related research, especially for in silico response element search, we tried to elucidate nuclear receptor mediated xenobiotic processing loops and direct future research.
Nakata
Kotoko
K
Advance Soft Corporation/IIS, University of Tokyo.
Tanaka
Yoshitomo
Y
Nakano
Tatsuya
T
Adachi
Tatsuhiko
T
Tanaka
Hiroshi
H
Kaminuma
Tsuguchika
T
Ishikawa
Toshihisa
T
D000818:Animals; D019295:Computational Biology / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D008954:Models, Biological; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015262:Xenobiotics / Q000378:metabolism / Q000493:pharmacokinetics*
D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics