Yost G S, Horstman M G, el Walily A F, Gordon W P, Nelson S D
Toxicol Appl Pharmacol. 1985 Sep 15;80(2):316-22. doi: 10.1016/0041-008x(85)90089-4.
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-alpha-(2-methylhydrazino)-p-[alpha, alpha-2H2]toluamide (d2-procarbazine), or at the methyl position, N-isopropyl-alpha-(2-[alpha, alpha, alpha-2H3]methylhydrazino)-p-toluamide (d3-procarbazine). Spermatogenesis decreases caused by d3-procarbazine were essentially the same as with procarbazine in mice (66% of controls at a dose of 200 mg/kg), but d2-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 methyl-labeled analog, indicate the requirement for regioselective oxidative metabolism of procarbazine at the benzylic position prior to the toxic event.
丙卡巴肼在雄性小鼠中呈剂量依赖性地降低精子发生。在精子计数测定前18天给予400mg/kg的剂量时，观察到精子发生显著减少（为对照组的44%）。丙卡巴肼在体内未引起显著的急性杀精活性。因此，丙卡巴肼相关的精子发生减少被用作发育中的精子细胞毒性的指标。合成了丙卡巴肼类似物，其中在苄基位置用氘取代氢，即N-异丙基-α-（2-甲基肼基）-对-[α，α-2H2]甲苯酰胺（d2-丙卡巴肼），或在甲基位置，即N-异丙基-α-（2-[α，α，α-2H3]甲基肼基）-对甲苯酰胺（d3-丙卡巴肼）。d3-丙卡巴肼引起的精子发生减少与小鼠中丙卡巴肼引起的基本相同（在200mg/kg剂量下为对照组的66%），但d2-丙卡巴肼对发育中的精子细胞无毒（在200mg/kg剂量下为对照组的99%）。苄基位置的氘取代导致毒性降低，再加上甲基标记类似物没有作用，表明在毒性事件发生之前，丙卡巴肼在苄基位置需要区域选择性氧化代谢。
