Batzinger R P, Bueding E, Reddy B S, Weisburger J H
Cancer Res. 1978 Mar;38(3):608-12.
A new broad-spectrum antiparasitic agent, 4-isothiocyano-4'-nitrodiphenylamine, is devoid of mutagenic activity in vitro, either alone or in the presence of activating enzymes of rat liver. However, six species of mammals receiving this drug excrete as as yet unidentified mutagenic metabolite. Several observations suggested that one or several constituents of the enteric bacterial flora, rather than the metabolic activities of the host, are involved in the formation of this mutagen. Unequivocal demonstration for such a mechanism was provided by germ-free rats that do not form this metabolite, in contrast to their conventional littermates. Only a relatively moderate and apparently quite selective reduction in the total number of microorganisms of the intestinal flora is needed to elminate this mutagenic transformation. For example, following administration of a single dose of erythromycin or erythromycylamine, conversion of the isothiocyanate to a mutagen can be prevented completely, while antiparastitic activity is maintained. There is no obligatory association between chemotherapeutic activity and the formation of the mutagenic metabolite, and these two activities can be dissociated completely. This suggests a new approach for increasing the safety of pharmacological agents.
一种新型广谱抗寄生虫药物4-异硫氰酸基-4'-硝基二苯胺，无论单独使用还是在存在大鼠肝脏激活酶的情况下，在体外均无诱变活性。然而，接受这种药物的六种哺乳动物会排泄出一种尚未鉴定的诱变代谢物。多项观察结果表明，肠道细菌菌群的一种或几种成分，而非宿主的代谢活动，参与了这种诱变剂的形成。无菌大鼠与它们的常规同窝仔鼠不同，不会形成这种代谢物，这为这种机制提供了明确的证据。只需相对适度且明显具有选择性地减少肠道菌群的微生物总数，就能消除这种诱变转化。例如，单次给予红霉素或红霉胺后，异硫氰酸盐向诱变剂的转化可被完全阻止，同时抗寄生虫活性得以维持。化疗活性与诱变代谢物的形成之间不存在必然联系，这两种活性可以完全分离。这提示了一种提高药物安全性的新方法。
