The Biochemical Basis for the Differential Sensitivity of Intestinal Mucosa and Bone Marrow to 6-thioguanine.

The differential sensitivity of mammalian tissues to 6-thioguanine was studied by measuring the metabolic fate of this agent in the bone marrow and intestinal mucosa of rabbits. After the injection of thioguanine-S35, intestinal mucosa contained, per gram of tissue, a sixteen-fold higher level of 6-thiouric acid, but less than one-half the quantity of thioguanine mononucleotide than did bone marrow. Thioguanine nucleotide pyrophosphorylase activity in bone marrow extracts was fivefold greater than in extracts prepared from intestinal mucosa. In contrast, thiouric acid was formed by extracts of intestinal mucosa but not by those of bone marrow. These data suggest that the extreme sensitivity of bone marrow to thioguanine is attributable to the relatively rapid conversion of this agent to the nucleotide level, coupled with an inability to catabolize this molecule to inactive products. The resistance of intestinal mucosa to 6-thioguanine appears to have a twofold basis: (a) a relatively lower nucleotide pyro phosphorylase activity and (6) an active mechanism for conversion of the drug to 6-thiouric acid.