Altered expression of CYP in TSOD mice: a model of type 2 diabetes and obesity.
To investigate the pharmacokinetic characteristics in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of type 2 diabetes and obesity, the expressions of major hepatic CYP enzymes in TSOD and TSNO (Tsumura, Suzuki, non-obesity; control) mice were compared. The 7-month-old TSOD mice, which represented severe obesity/diabetes-related pathophysiology, showed higher expressions of Cyp2c and Cyp3a compared with TSNO mice, while those of Cyp1a and Cyp2e were lower. Cyp3a metabolic activity was also higher in TSOD mice. In the 7-month-old liver, pregnane X receptor (PXR) (nuclear receptor) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) (cofactor) mRNA expression were higher in TSOD mice, possibly playing a role in the altered expression of Cyp3a. This specifically altered CYP expression in TSOD mice suggests that the biotransformation of drugs metabolized by these CYP enzymes differs from that in normal animals. Based on these findings, further investigation on the relationship between altered CYP expression and pathophysiology may be useful in elucidating changes in pharmacokinetics in obese/diabetic patients.
Kudo
T
T
Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Tokyo, Japan.
Shimada
T
T
Toda
T
T
Igeta
S
S
Suzuki
W
W
Ikarashi
N
N
Ochiai
W
W
Ito
K
K
Aburada
M
M
Sugiyama
K
K
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014229:Triazolam / Q000378:metabolism / Q000493:pharmacokinetics
D007527:Isoenzymes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014229:Triazolam; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System