Irreversible suppression of growth hormone-dependent cytochrome P450 2C11 in adult rats neonatally treated with monosodium glutamate.
Neonatal exposure to monosodium glutamate (MSG) permanently blocks growth hormone (GH) secretion, which results in the development of a well-defined syndrome characterized by stunted body growth, obesity and impaired drug metabolism. We have found that restoration of the normal masculine circulating profile of GH (i.e., six daily pulses) by use of an external pumping apparatus is ineffective in restoring the normal expression of hepatic cytochrome P450 2C11, a major GH-dependent drug and steroid metabolizing enzyme that is eliminated by MSG treatment. Moreover, administering GH at two, four or seven plasma pulses per day with amplitudes ranging from physiologic to 7 times normal were similarly ineffective in restoring the expression (at both an activity and mRNA level) of the cytochrome. Additionally, multicytochrome P450-dependent hexobarbital hydroxylase was also unresponsive to GH administration in the MSG-treated rats. Because GH replacement was unable to correct the enzyme defects, our results suggest that the developmental abnormalities produced by neonatal MSG are not simply a result of a GH deficiency per se, but are due to an irreversible insensitivity of the target cell to GH.
Laboratory of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, Philadelphia.
B H
BH
Shapiro
N A
NA
Pampori
P A
PA
Ram
D J
DJ
Waxman
D000818:Animals; D000831:Animals, Newborn; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006130:Growth Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D013006:Growth Hormone / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011673:Pulsatile Flow; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012970:Sodium Glutamate / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C021352:hexobarbital hydroxylase; D012970:Sodium Glutamate