We have reported that greater than 50% of normal healthy cats receiving 150mg daily of propylthiouracil (PTU) develop a lupus-like syndrome within 6 weeks. This syndrome is characterized by lethergy, anoerexia, lymphadenopathy, severe hemolytic anemia, positive Coombs' test and antunuclear antibodies. The induction of this disease is dose-dependent and requires a free sulfur group on PTU. Methimizole (MMI) another sulfur containing antithyroid drug, induces ANA in over 1/3 of hyperthyroid cats receiving 15mg/day for hyperthyroidism. However, this drug has failed to produce any clinical signs of a lupus-like syndrome. Remarkably, both PTU and MMI induce the formation of anti-native DNA antibodies, and possibly other autoantibodies against nonhistone nuclear protein(s). A 3 year research program with 4 specific aims is planned. 1) To determine if a difference in PTU disposition and metabolism between responder and nonresponder cats accounts for the difference in susceptability to this disease. Both IV and oral PTU pharmacolinetics will be determined by HPLC developed to measure PTU and its putative metabolites in serum and urine. 2) To determine if metabolism of PTU is a protective or inducing factor in this disease the putative metabolites of PTU will be identified and quantitated. The end-product of oxidative desulfuration, propyluracil, the S-methyl and glucuronidated metabolites of PTU will be assayed for by HPLC in serum and urine collections over 24 hours in responder and nonresponder cats. 3) To determine if MMI induces autoantibody formation, without the clinical sequelle of PTU induced lupus, in normal healthy cats as it does in hyperthyroid cats. Normal cats will receive 30-60mg/day of MMI for 3 months and be monitored for the induction of ANA and clinical disease. 4) To identify the Ig class and fine antigenic specificity of these PTU and MMI induced antinuclear antibodies and PTU induced anti-RBC antibodies. Monoclonal mouse anti-cat gamma and mu chain antibodies will be used in an ELISA to determine anti-native and denatured DNA and anti-histone antibodies and in the Western blot to determine specific histone fraction and nonhistone nuclear protein antibodies. These assays will determine if there is a difference in specificity, titer, or class of Ig between PTU and MMI induced autoantibodies and determine the potential role these antibodies have in the pathogenesis of this drug-induced lupus-like disease.
