Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet.
OBJECTIVE
Changes in physiological, pathophysiological, and/or nutritional conditions often alter the expression of drug-metabolizing enzymes. In this study, we investigated obesity-induced changes in hepatic cytochrome P450 (P450) levels using nutritionally obese mice.


METHODS
To induce obesity, mice were fed a high-fat diet or treated with gold thioglucose, which impairs ventromedial hypothalamus. Total RNAs and microsomal and nuclear proteins were prepared from the liver of these mice, and mRNA and protein levels of P450s and transcription factors were determined.


RESULTS
Among P450s examined, the constitutive expression of CYP3As was drastically reduced at both mRNA and protein levels by nutrition-induced obesity. One-week administration of a high-fat diet also reduced hepatic CYP3As. However, changes in nuclear receptors involved in the transcriptional regulation of CYP3A genes were not correlated with that of CYP3As. Obese mice induced by gold thioglucose exhibited a different expression profile of hepatic P450s with no significant change in CYP3As.


CONCLUSIONS
High-fat diet-induced changes in energy metabolism, which eventually result in obesity, modulate the hepatic expression profile of P450s, particularly CYP3As. Alternatively, the accumulation of a certain component in a high-fat diet may directly attenuate the CYP3A expression, suggesting a clinically important drug-diet interaction.
Yoshinari
Kouichi
K
Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Takagi
Shunsuke
S
Yoshimasa
Teruyasu
T
Sugatani
Junko
J
Miwa
Masao
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D006051:Aurothioglucose; D051544:Cytochrome P-450 CYP3A / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D003907:Dexamethasone / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004917:Erythromycin / Q000378:metabolism; D007421:Intestine, Small / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology; D009765:Obesity / Q000139:chemically induced / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004041:Dietary Fats; D008565:Membrane Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C400322:cytochrome P-450 CYP2C subfamily; D006051:Aurothioglucose; D004917:Erythromycin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2