Alterations of [14C]azoxymethane metabolism by pretreatment with pyrazole, an inhibitor of alcohol dehydrogenase, were studied in male F344 rats. Whereas control animals exhaled approximately 36% of the [14C]azoxymethane dose (10.5 mg/kg) in 6 hr as 14CO2, rats pretreated with pyrazole (40 mg/kg) exhaled approximately 3.5%. Pretreatment with pyrazole (360 mg/kg) caused a complete inhibition of exhaled 14CO2 for at least 6 hr. After 48 hr the amount of exhaled 14CO2 comprised approximately 50% of the dose in the controls, and 26 and 20% for the 40- and 360-mg/kg pyrazole-pretreated rats, respectively. [14C]Methylamine, [14C]urea, and [14C]methylazoxymethanol were detected in the urines of control rats. Pretreatment with pyrazole (40 mg/kg) caused a 2.5-fold increase in urinary methylazoxymethanol; pretreatment with pyrazole (360 mg/kg) increased the urinary level of azoxymethane some 2.5- to 3-fold. In contrast to controls and 40-mg/kg pyrazole-pretreated rats, 360-mg/kg pyrazole-pretreated animals showed increased urinary excretion of [14C]methylamine and continued excretion of [14C]methylazoxymethanol and unmetabolized [14C]azoxymethane during the 24- to 48-hr period after [14C]azoxymethane administration. Washed liver microsomes from pyrazole-treated rats converted azoxymethane to methylazoxymethanol at the same rate as controls, but the hydroxylation could be inhibited by the addition of pyrazole to the incubation system.
These results show that pyrazole inhibits the metabolism of azoxymethane at at least two steps. At 40 mg/kg, pyrazole inhibits the oxidation of methylazoxymethanol, presumably by blocking alcohol dehydrogenase. At 360 mg/kg, pyrazole blocks this reaction and inhibits the hydroxylation of azoxymethane.
This work was supported in part by Grant CA 15400 from the National Cancer Institute through the National Large Bowel Cancer Project and by Contract N01 CP 75948 with the National Cancer Institute.