Abstract
Neonatal administration of monosodium glutamate (MSG) can produce latently expressed defects in drug metabolism and growth hormone secretion as well as stunted growth and obesity. Instead of secreting growth hormone in the masculine episodic profile, plasma hormone levels are generally undetectable in affected adult male rats. Moreover, male-specific isoforms of cytochrome P450 (P450; e.g., CYP2C11 and CYP3A2), whose combined levels comprise the bulk of the total hepatic P450 in adult male rats, are similarly undetectable in these animals. Since “signaling elements” in the masculine episodic growth hormone profile are solely responsible for the elevated characteristic male-like expression levels of CYP2C11 and CYP3A2, suppression of the isoforms in the MSG-treated rats appeared to be caused by the simple absence of the hormone from the circulation. However, the reported failures of restored physiologic masculine growth hormone profiles to correct the P450 defects suggested the occurrence of direct MSG-induced liver damage independent of the well known hypothalamic lesions produced by the amino acid. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent noncompetitive N-methyl-d-aspartate receptor antagonist of glutamate, completely prevented the adverse effects of neonatal MSG treatment on P450 expression, growth hormone secretion, and growth parameters, indicating that the amino acid-induced defects are solely a result of neuronal (i.e., hypothalamic) damage produced at the time of MSG exposure. The irreversibility of the P450 damage is described as resulting from secondary defects initially induced by the neuronal lesions.
Footnotes
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↵1 Irrespective of the measured endpoint, the effects of the NaCl vehicle treatment and phosphate-buffered saline vehicle treatment were indistinguishable so that all results from both groups were combined into a single “vehicle” treatment group.
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This work was supported by National Institutes of Health Grant HD16358.
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DOI: 10.1124/jpet.102.034785
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- P450
- cytochrome P450
- MSG
- monosodium glutamate
- MK-801
- dizocilpine maleate
- Received February 14, 2002.
- Accepted April 8, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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