Expression of CYP3A23/1, CYP3A2, PXR, CAR and HNF4alpha in large-for-gestational-age neonatal rats.
BACKGROUND
The available information about hepatic drug-metabolizing enzymes in the large-for-gestational-age (LGA) neonate is limited.


OBJECTIVE
To determine whether LGA status alters expression of the cytochrome p450 enzymes, CYP3A23/1 and CYP3A2, and nuclear receptors PXR, CAR and HNF4alpha.


METHODS
Appropriate-for-gestational-age (AGA) and LGA pups from 10 litters of rats (n=15 pups/group) were used. Hepatic expression levels of CYP3A23/1, CYP3A2, pregnane X receptor (PXR), constitutive androstane receptor (CAR), and HNF4alpha mRNA were detected by quantitative real-time RT-PCR. Protein expression was determined immunohistochemically and expression levels were evaluated using staining intensity scores and percentage of positive hepatocytes.


RESULTS
The mean body weights of AGA and LGA rat pups were 6.20 +/- 0.49 and 7.77 +/- 0.70 g (mean +/- SD), respectively (P < 0.001). Liver weight/body weight ratios trended higher in the LGA group (5.18 +/- 0.50%, mean +/- SD) than in the AGA group (4.90 +/- 0.01%, mean +/- SD), but the difference was not significant. CYP3A2 mRNA levels were higher in LGA than in AGA pups (P < 0.05), but there were no group differences in CYP3A23/1 mRNA levels. HNF4alpha levels were also higher in the LGA group (P < 0.05), but PXR and CAR mRNA levels did not differ between the groups. The staining intensity and frequency of CYP3A23/1-positive and HNF4alpha-positive hepatocytes differed between LGA and AGA pups, whereas no significant differences in CYP3A2 or CAR protein expression were observed between groups.


CONCLUSIONS
LGA status affects the hepatic expression of CYP3A23/1, CYP3A2, and HNF4alpha, suggesting that further research on this issue is warranted.
Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, People's Republic of China.
Shaoqing
S
Ni
Xiumin
X
Wang
Jue
J
Wang
Su
S
Zeng
Zhengyan
Z
Zhao
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001835:Body Weight / Q000502:physiology; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008099:Liver / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis*; D009929:Organ Size / Q000502:physiology; D011247:Pregnancy; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D011987:Receptors, Steroid / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*
D000090702:Constitutive Androstane Receptor; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A