[Functional analysis of drug metabolizing enzymes using gene knockout animals].
Several gene knockout mice have been widely used to analyze the role of drug-metabolizing enzymes in pharmacologic and physiologic responses. The metabolic shift of endogenous and exogenous compounds causes pharmacologic and physiologic alterations. Microsomal epoxide hydrolase (mEH)-null mice are less susceptible to the skin tumorigenesis, splenic immunotoxicity, and embryonic toxicity of 7,12-dimethylbenz[a] anthracene (DMBA). The production of DMBA-3,4-diol is detected in the target organs of wild-type mice, but not in those of mEH-null mice. Soluble epoxide hydrolase (sEH)-null mice exhibit markedly reduced rates of epoxyeicosatrienoic acid conversion to dihydroxyei-cosatrienoic acid in the liver and kidney. Furthermore, sEH-null male mice have a lower blood pressure phenotype compared with male wild-type mice, suggesting the importance of sEH in blood pressure regulation. Nuclear bile acid receptor, farnesoid X receptor (FXR)-null mice are distinguished from wild-type mice by elevated bile acid levels in the liver and serum. However, hepatic lithocholic acid (LCA) levels are lower in LCA-fed FXR-null female mice compared to those in wild-type female mice. Furthermore, FXR-null female mice are less susceptible to liver damage by LCA compared with female wild-type mice. Marked increases in hepattic LCA-sulfating activity and hepatic hydroxysteroid sulfotransferase and biliary sulfated bile acid levels are detected in FXR-null female mice, suggesting the protective role of hydroxysteroid sulfotransferase in LCA-induced liver damage. These and other studies indicate that mice null for drug-metabolizing enzymes and nuclear receptors are of great value in the study of the role of drug-metabolizing enzymes in pharmacologic and physiologic responses.
Miyata
Masaaki
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000502:physiology*; D005260:Female; D008095:Lithocholic Acid / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D015127:9,10-Dimethyl-1,2-benzanthracene; D001095:Arachidonic Acids; D004268:DNA-Binding Proteins; D004851:Epoxide Hydrolases; D008095:Lithocholic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C028152:alcohol sulfotransferase