Drug-induced modulations of hepatic heme metabolism. Neurological consequences.
Administration of the porphyrinogenic agent DDEP to PB-pretreated rats results in acute hepatic heme depletion, which is a characteristic of acute hepatic porphyria. Such acute heme depletion is associated with impaired hepatic tryptophan degradation and enhanced serotonergic tone in the CNS. We showed that intestinal motility in these rats is also significantly decreased, indicating that the serotonergic tone of the enteric nervous system may also be enhanced. In addition, the marked hepatic accumulation of glucogenic precursors, observed in parallel, indicates that the elevated tryptophan levels may also block hepatic glucogenesis. The clinical implications of these findings to acute heme-deficient states, such as the acute hepatic porphyrias, was discussed.
Department of Pharmacology, University of California, San Francisco 94143.
M A
MA
Correia
D A
DA
Litman
J M
JM
Lunetta
D000818:Animals; D001921:Brain / Q000502:physiology*; D005746:Gastric Emptying; D005943:Gluconeogenesis; D006418:Heme / Q000378:metabolism*; D007421:Intestine, Small / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000503:physiopathology; D008954:Models, Biological; D011164:Porphyrias / Q000503:physiopathology; D011739:Pyrimethamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism
D012701:Serotonin; C013909:etoprine; D006418:Heme; D014364:Tryptophan; D011739:Pyrimethamine