In Vivo and In Vitro Induction of Cytochrome P450 3A4 by Thalidomide in Humanized-Liver Mice and Experimental Human Hepatocyte HepaSH cells.
Shotaro UeharaNorie MurayamaYuichiro HiguchiMakiko ShimizuHiroshi SuemizuFrederick Peter GuengerichHiroshi YamazakiPublished in: Chemical research in toxicology (2024)
Autoinduction of cytochrome P450 (P450) 3A4-mediated metabolism of thalidomide was investigated in humanized-liver mice and human hepatocyte-derived HepaSH cells. The mean plasma ratios of 5-hydroxythalidomide and glutathione adducts to thalidomide were significantly induced (3.5- and 6.0-fold, respectively) by thalidomide treatment daily at 1000 mg/kg for 3 days and measured at 2 h after the fourth administration (on day 4). 5-Hydroxythalidomide was metabolically activated by P450 3A4 in HepaSH cells pretreated with 300 and 1000 μM thalidomide, and 5,6-dihydroxythalidomide was detected. Significant induction of P450 3A4 mRNA expression (4.1-fold) in the livers of thalidomide-treated mice occurred. Thalidomide exerts a variety of actions through multiple mechanisms following bioactivation by induced human P450 3A enzymes.
Keyphrases
- induced apoptosis
- endothelial cells
- cell cycle arrest
- high glucose
- diabetic rats
- high fat diet induced
- oxidative stress
- pluripotent stem cells
- endoplasmic reticulum stress
- liver injury
- drug induced
- signaling pathway
- physical activity
- high resolution
- mass spectrometry
- adipose tissue
- cell proliferation
- wild type
- newly diagnosed
- atomic force microscopy