Liver microsomal inactivation of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone as an inhibitor of ribonucleotide reductase.
Studies were carried out to determine the effects of preincubation of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ) with hepatic microsomes on the ability of MAIQ to inhibit CDP reductase activity in vitro. An aliquot from the 100,000 x g supernatant fraction from this incubation was used in the CDP reductase assay. MAIQ incubated in the absence of microsomes inhibited CDP reductase activity in a dose-dependent manner. At high MAIQ concentration (5 microM) CDP reductase activity was inhibited 95%. When MAIQ (5 microM) was first incubated in the presence of hepatic microsomes and NADPH, CDP reductase activity was inhibited only 30%. This attenuation of MAIQ inhibition was dependent on time of incubation and microsomal protein concentration and showed an obligatory requirement for NADPH or NADH. Significant attenuation was observed at pyridine nucleotide concentrations as low as 0.1 mM. Heat denaturation of microsomal proteins inactivated their ability to attenuate the MAIQ inhibition. Microsomes prepared from Ehrlich tumor cells were ineffective as inactivators of MAIQ. Results of our studies show that hepatic microsomes contain an enzyme(s) which can inactive MAIQ as an inhibitor of CDP reductase.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004790:Enzyme Induction; D006358:Hot Temperature; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D007546:Isoquinolines; D013882:Thiosemicarbazones; C002526:1-formylisoquinoline thiosemicarbazone; D009249:NADP; C013118:4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone; D003577:Cytochrome P-450 Enzyme System; D012264:Ribonucleotide Reductases