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Formation of a Mutagenic Drug Metabolite by Intestinal Microorganisms¹

Departments of Pathobiology and Pharmacology and Experimental Therapeutics, The Johns Hopkins University, Baltimore, Maryland 21205 [R. P. B., E. B.], and Naylor Dana Institute of Disease Prevention, Valhalla, New York 10595 [B. S. R., J. H. W.]

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 an 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 eliminate 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 antiparasitic 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.

¹ Supported by grants and contracts from NIH (CA 18251, GM-16492, and NCI-CI-332 06). the Agency of International Development, and the Edna McConnel Clark Foundation.

² To whom requests for reprints should be addressed.