YoungHyp mice malabsorb phosphate from the jejunum at 4 weeks of age. This has been attributed to both low plasma levels of 1,25-dihydroxyvitamin D and to intestinal resistance to stimulation by 1,25-dihydroxyvitamin D. To differentiate between these two hypotheses, 4 week old normal andHyp mice were treated with 0, 17, 50, or 150 ng/kg/day of 1,25-dihydroxyvitamin D(3) by Alzet osmotic mini pumps (n=10-12/group). After 4 days, the jejunum was isolated by sutures and 0.5 ml 2 mM Na(2)HPO(4) in 150MM: NaCl with 1.0 µCi(32)PO(4) was injected into the lumen. After 8 min, plasma, jejunal tissue and lumenai contents were measured for(32)P content. Absorption was measured as counts removed from the lumen. Both normal andHyp mice responded to the 1,25-dihydroxyvitamin D(3) with increased absorption, increased tissue(32)P and increased plasma(32)P.Hyp mice responded less than normal mice to the 50 ng/kg/day dose in plasma(32)P levels (significant dose by genotype interaction,P<0.05). Plasma was pooled by genotype and dose for the measurement of plasma 1,25-dihydroxyvitamin D. This yielded 13 samples (7 normal and 6Hyp). Absorption of(32)P (r=0.75, p=0.002) and jejunal tissue content of(32)P (r=0.66, p=0.02) were correlated to plasma 1,25-dihydroxyvitamin D. Analysis of covariance revealed a significant difference in phosphate absorption between normal andHyp mice (p=0.02). In conclusion, there is a partial resistance of intestinal phosphate absorption to 1,25-dihydroxyvitamin D stimulation.