Induction of bacterial mutations by aminopyrazoles, compounds which cause mammary cancer in rats

An aminopyrazole PD 71627 (5-amino-1,3-dimethyl-1H-pyrazol-4-yl) (2-fluorophenyl)methanone, and two amide derivatives, PD 108298, N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl]-2- ([3-(2-methyl-1- piperidinyl)-propyl]amino) acetamide-(Z)-2-butanedioate (1:2), and PD 109394, 2-(diethylamino)-N-[4-(2- fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl]acetamide hydrochloride, proposed neuroleptic drugs, were found to elicit mammary adenocarcinomas in male rats after 13 weeks of treatment. These compounds were assessed for their ability to induce His+ revertants (rev) in five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) in the presence and absence of S9 activation. All were found to be potent mutagens in TA98 and TA100 after a 20 min pre-incubation with Aroclor 1254-induced rat liver S9. However, the activity of the amino-pyrazole PD 71627 was much greater than the amide derivatives, PD 108298 or PD 109394, with activity of 11,800 rev/mumol, 670 rev/mumol, and 230 rev/mumol respectively in TA100, the strain showing the greatest response. A comparison of liver S9 fractions from rats untreated or pretreated with phenobarbital (PB) or Aroclor 1254 showed that S9 from animals pretreated with PB provided the greatest activation capability for the aminopyrazole PD 71627 (59,300 rev/mumol in TA100). Three structural analogs of the aminopyrazole PD 71627, two without the amine and one with a methyl substituent on the amine, were compared with PD 71627 for induction of revertants in TA100 and TA98. The compounds without the amine had no mutagenic activity while the methyl derivative induced 3100 rev/mumol in TA100 after preincubation with Aroclor 1254-induced S9. This confirmed that the amine on the pyrazole ring was required for mutagenic activity. The results of these studies support the hypothesis that these compounds cause cancer in animals as a result of DNA damage.