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)dinilrilo)bis(3–aminoguaniidine) (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