Sex differences in the circadian variation of cytochrome p450 genes and corresponding nuclear receptors in mouse liver.
Sex differences and circadian variation are two major factors that affect the expression of drug-processing genes. This study aimed to examine sex differences in the circadian variation of hepatic cytochrome P450 (Cyp) genes and corresponding nuclear receptors. Adult mice were acclimated to environmentally controlled facilities for 2 wks, and livers were collected every 4 h during a 24-h period. Total RNA and protein were isolated and subjected to real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The mRNA expression of the aryl hydrocarbon receptor (AhR) and AhR-regulated Cyp1a1 and Cyp1a2 were higher in females and higher during the light phase. The mRNA expression of constitutive and rostane receptor (CAR) and CYP2B10 protein was female-predominant and higher in the dark phase. Pregnane X receptor (PXR) peaked around 18:00 h, but PXR-regulated Cyp3a11 and Cyp3a25 were higher at 10:00 h, without apparent sex dimorphism at protein levels. Peroxisome proliferator-activated receptor-α (PPARα), Cyp4a10, and Cyp4a14 were higher in females and peaked between 14:00 and 18:00 h. The mRNA levels of farnesoid X receptor (FXR), Cyp7a1, and Cyp27a1 peaked around 18:00 h and CYP7A1 protein was higher during the dark phase and higher in females. Cyp7b1(male-predominant) and Cyp2a4 (female-predominant) both showed circadian variation. Circadian variation of hepatic clock genes such as nuclear receptor Rev-erbα, cryptochrome 1 (Cry1), and brain muscle ARNT-like protein 1 (Bmal1) showed distinct patterns. Sex differences and circadian rhythmicity of Cyp genes and corresponding nuclear receptors exist in mouse liver that could impact xenobiotic metabolism and toxicity at different times of the day.
Key Laboratory of Basic Pharmacology of Guizhou, Zunyi Medical College , Zunyi , China .
Yuan-Fu
YF
Lu
Tao
T
Jin
Yasha
Y
Xu
Dan
D
Zhang
Qin
Q
Wu
Yu-Kun Jennifer
YK
Zhang
Jie
J
Liu
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002940:Circadian Rhythm; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; C512110:Cyp4a10 protein, mouse; C436963:Cyp4a14 protein, mouse; D008565:Membrane Proteins; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; C517429:Cyp3a25 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse