Effect of the brachymorphic trait in mice on xenobiotic sulfate ester formation

Mice carrying the recessive mutation brachymorphic have been shown previously to have a reduced capacity to synthesize 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the required coenzyme in sulfation reactions [K. Sugahara and N. Schwartz, Proc. natn. Acad. Sci. U.S.A. 76, 6615 (1979)]. The capacity of the liver cytosol fractions from brachymorphic (bm/bm) mice or their phenotypically normal littermates (+/+ or +/bm) to catalyze the formation of sulfate esters of [3H]estrone and [14C]p-nitrophenol in vitro was determined. When PAPS was added to the reaction, the rates of sulfate ester formation catalyzed by the two cytosol fractions were similar. In contrast, when PAPS was generated in situ from ATP and SO(4)2-, the rates of sulfate ester formation catalyzed by the brachymorphic cytosol were only 4-22% of the rates catalyzed by the cytosol fraction from normal mice. The hepatic cytosol fraction from brachymorphic mice incorporated less 35SO(4)2- into PAPS than that catalyzed by cytosol of normal mice. [14C]p-Nitrophenol (1.5 mumoles/kg) was eliminated from brachymorphic and normal mice as urinary conjugates; in normal mice, 73% of the urinary radioactivity was p-nitrophenyl sulfate, while in the brachymorphic mice only 33% of the urinary excretion was the sulfate ester. Brachymorphic mice have a reduced capacity for synthesizing sulfate esters of xenobiotics in vitro and in vivo, which is attributable to their reduced synthesis of PAPS.