title: Inhibition of rat brain pyruvate dehydrogenase by thiamine analogs.
abstract: The effects of thiamine thiazolone (TT) and thiamine thiazolone pyrophosphate (TTPP) on the in vitro and in vivo inhibition of pyruvate dehydrogenase complex (PDHC) from rat cortex and hippocampus were characterized. TTPP decreased PDHC activity in vitro but had no effect in vivo following its direct chronic administration via osmotic mini-pumps into the brains of behaving rats. In contrast, TT had no direct effect in vitro following a differential centrifugation purification of the mitochondrial PDHC fraction, but decreased PDHC activity in vivo. Additional experiments demonstrated that the cytosolic fraction converted TT to TTPP which, in turn, inhibited PDHC in vitro. A mechanism is proposed to explain these effects that is consistent with a non-competitive inhibition of brain PDHC by TTPP.
authors.affiliation: Department of Pharmacology, Northeastern Ohio Universities, College of Medicine, Rootstown 44272.
authors.forename: C T
authors.initials: CT
authors.lastname: Kandiko
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: B K
authors.initials: BK
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013835:Thiamine Pyrophosphate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D011768:Pyruvate Dehydrogenase Complex; C057793:thiamine thiazolone; C014222:thiamine thiazolone pyrophosphate; D013835:Thiamine Pyrophosphate; D013831:Thiamine