title: Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate.
abstract: Perinatal exposure of rats and mice to the typically reported 4mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform--all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2mg/g bd wt on alternate days for the first 9days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70-80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible.
authors.affiliation: Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
authors.forename: Rajat Kumar
authors.initials: RK
authors.lastname: Das
authors.affiliation: Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Giffear
authors.affiliation: Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA. Electronic address: shapirob@vet.upenn.edu.
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Shapiro
mesh_terms: D021581:Active Transport, Cell Nucleus; D000367:Age Factors; D000418:Albumins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction; D005260:Female; D005421:Flavoring Agents / Q000633:toxicity*; D013006:Growth Hormone / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000378:metabolism; D012727:Sex Characteristics; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects; D012970:Sodium Glutamate / Q000633:toxicity*; D039181:Steroid 16-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D054875:Ubiquitination
chemical_list: D000418:Albumins; D002352:Carrier Proteins; D005421:Flavoring Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C491408:Socs2 protein, rat; C494097:Stat5b protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C089877:Cyp2c6v1 protein, rat; C493085:Cyp2c7 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase; C051815:somatotropin-binding protein; D012970:Sodium Glutamate
keywords: CYP2C11; Growth hormone; MSG; SOCS2; STAT5b; Sexual dimorphism