MECHANISTIC STUDIES ON GENOTOXICITY AND CARCINOGENICITY OF SALICYLAZOSULFAPYRIDINE AN ANTIINFLAMMATORY MEDICINE

Salicylazosulfapyridine (SASP), which has been in clinical use for ove r 50 years, was reported by the National Toxicology Program to increas e rat (F344 strain) urinary bladder and mouse (B6C3F(1) hybrid) liver tumors under ad libitum (AL) feeding conditions, while under a feed re striction (FR) regimen, these tumors were not increased. The present i nvestigations were undertaken to assess the implications of these resu lts for the safety of SASP in humans. SASP and its 2 major metabolites , 5-aminosalicylic acid (ASA) and sulfapyridine (SP) were tested for i n vivo induction of micronuclei in mouse bone marrow cells with or wit hout prefolic treatment and for in vivo formation of DNA adducts in ra t and mouse liver and urinary bladder. None exhibited mutagenicity or DNA reactivity. SASP and SP have induced sister chromatid exchanges an d micronuclei (MN) in cultured human lymphocytes in the absence of liv er activation enzymes and in B6C3F, mice (but not in rats) MN in bone marrow and peripheral RBC. Treatment with folate reduces the frequency of MN. Perhaps the short (28 days) RBC lifespan in mouse underlies th e sensitivity of this species. Thus, SASP without folate supplementati on is an aneuploidogen. In a 2-year study in AL fed SASP-treated (high dose 337.5 mg/kg) rats, urinary pH was increased and urinary specific gravity was reduced at 60 weeks. At the end, this SASP group showed u rothelial hyperplasia and papillomas in the urinary bladders of male r ats primarily. In the FR high dose SASP group, the hyperplasia was red uced from 82 % to 14 %. At the end of 2 years, the incidence of multio rgan leukemia was reduced in both AL and FR high dose SASP groups. Thu s, SASP caused intraluminal bladder changes in the rat (especially mal es) consisting of chronic urothelial stimulation, concretions, hyperpl asia which resulted in neoplasia. In the mouse, because of species dif ferences in liver ratios (mouse > rat) and, increasing (3 times higher ) liver perfusion in the mouse, compared to the rat, there was hepatoc ellular toxicity and resulting preneoplasia and neoplasia within 2 yea rs. These findings occurred in all AL SASP groups (flat curve without dose response); but were reduced under FR conditions. In this species, the multiorgan lymphoma incidence was reduced in both AL and FR high dose SASP groups. Thus, SASP and its major metabolites are not genotox ic. Folate deficiency associated with SASP administration is probably responsible for aneuploidy in lymphocytes and erythrocytes. SASP does not induce neoplasia directly in either livers, urinary bladders or ot her organs. Accordingly, SASP is judged to pose no carcinogenic risk t o humans.