INHIBITION OF GLUCOSE-6-PHOSPHATE PHOSPHOHYDROLASE BY 3-MERCAPTOPICOLINATE AND 2 ANALOGS IS METABOLICALLY DIRECTIVE

3-Mercaptopicolinae (3-MP) blocks gluconeogenesis from lactate, pyruva te, alanine, and other substrates through its inhibition of phosphoeno lpyruvate carboxykinase. Nevertheless, we observed increased glycogene sis, net glucose uptake, and glucose-6-P levels in livers perfused wit h glucose in the presence of 3-MP. In perfusions with 20 mM dihydroxya cetone, increased glycogenesis and decreased glucose production were o bserved with 3-MP. These metabolic effects suggested additional site(s ) of action of 3-MP. Further studies showed that 3-MP inhibits glucose -6-P phosphohydrolase activity of intact liver microsomes. Several com pounds with structural similarities to 3-MP (2-mercaptonicotinic acid, picolinic acid, cysteine, reduced glutathione, nicotinic acid, quinol inic acid, tryptophan, and pyridine) were tested for their effect on g lucose-6-P phosphohydrolase activity. Two of these compounds, 2-mercap tonicotinic acid and picolinic acid, were found to inhibit. In perfusi ons including 7.5 mM fructose, the addition of 3-MP, 2-mercaptonicotin ic acid, or picolinic acid increased glycogenesis, decreased glucose p roduction, and increased hepatic glucose-6-P concentrations. These obs ervations indicate that the inhibition of glucose-6-P phosphohydrolase may play a role in enhanced glycogenesis from glucose, dihydroxyaceto ne, and fructose in isolated livers from 48-h fasted rats perfused wit h 3-MP or certain sulfhydryl-containing and sulfhydryl-devoid analogs.