Inhibition by methylglyoxal bis(guanylhydrazone) of drug oxidation reactions catalyzed by mouse liver microsomes in vivo and in vitro.
The activity of coumarin 7-hydroxylase (coumarin 7-hydroxylation) was inhibited in B6 mouse liver after a single injection of methylglyoxal bis(guanylhydrazone (MGBG). The decrease in the activity in vivo was greatest (70%) one day after the drug injection and the hydroxylase activity in microsomal fraction prepared from livers of MGBG-treated B6 mice was still 25% decreased 5 days after the drug. The amount of cytochrome P-450 also was decreased in MGBG-treated livers with the same time-dependency as the inhibition of coumarin 7-hydroxylation. MGBG and its close derivative 1,1'-[methylethanediylidene)dinitrilo)bis(3-aminoguanidine) (MBAG) inhibited the activity in vitro of coumarin 7-hydroxylase, benzo(a)pyrene hydroxylase and 7-ethoxy 0-de-ethylase when microsomes were prepared from livers of untreated B6 mice. In every case MBAG was a better inhibitor than MGBG in vitro. The in vitro inhibition of MGBG of several drug metabolizing enzymes was not reversed when microsomes were preincubated with 1 mM putrescine, spermidine or spermine. These results suggest that the anti-cancer drug, MGBG, has a severe effect(s) on the drug metabolizing system at concentrations reached during the treatment of patients with MGBG.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D008935:Mitoguazone / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D008935:Mitoguazone