Acute inactivation of tryptophan hydroxylase by amphetamine analogs involves the oxidation of sulfhydryl sites.
The activity of rat hippocampal tryptophan hydroxylase was reduced from 30-60% 3 h after the administration of a 10-15 mg/kg dose of either fenfluramine, methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Tryptophan hydroxylase inactivated by these drug treatments could be reconstituted by a prolonged anaerobic incubation in the presence of 5 mM dithiothreitol and 50 microM Fe2+. Drug-inactivated enzyme obtained from rats killed 18 h after multiple doses of either D(+)- or L(-)-MDMA could not be similarly restored. These observations suggest that the rapid decrease in central tryptophan hydroxylase activity induced by amphetamine analogs results from the reversible oxidation of a sulfhydryl site(s) within the enzyme molecule, whereas the irreversible decrease in enzymatic activity measured 18 h after multiple-dose MDMA treatment may reflect serotonergic toxicity.
Stone
D M
DM
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Johnson
M
M
Hanson
G R
GR
Gibb
J W
JW
D000662:Amphetamines / Q000494:pharmacology*; D000693:Anaerobiosis; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000201:enzymology; D007501:Iron / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000032:analysis*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
D000662:Amphetamines; D013438:Sulfhydryl Compounds; D007501:Iron; D014365:Tryptophan Hydroxylase; D004229:Dithiothreitol