Procarbazine spermatogenesis toxicity: Deuterium isotope effects point to regioselective metabolism in mice

Abstract

Procarbazine was shown to decrease spermatogenesis in male mice in a dose-dependent manner. Significant decreases (44% of controls) in spermatogenesis were observed when a dose of 400 mg/kg was administered 18 days prior to determination of sperm count. Procarbazine caused no significant acute spermatocidal activity in vivo. Procarbazine-associated decreases in spermatogenesis were thus used as an index of toxicity to developing spermatid cells. Procarbazine analogs were synthesized that had deuterium substituted for hydrogen at the benzylic position, N-isopropyl-α-(2-methylhydrazino)- p-[α,α- 2H 2]toluamide ( d 2 -procarbazine), or at the methyl position, N-isopropyl-α-(2-[α,α,α- 2H 3]methylhydrazino)- p-toluamide ( d 3 -procarbazine). Spermatogenesis decreases caused by d 3-procarbazine were essentially the same as with procarbazine in mice (66% of controls at a dose of 200 mg/kg), but d 2-procarbazine was nontoxic to developing sperm cells (99% of control at a dose of 200 mg/kg). The decrease in toxicity caused by deuterium substitution at the benzylic position, coupled with the absence of an effect with the methyllabeled analog, indicate the requirement for regioselective oxidative metabolism of procarbazine at the benzylic position prior to the toxic event.