Mechanistic studies on genotoxicity and carcinogenicity of salicylazosulfapyridine an anti-inflammatory medicine.
Salicylazosulfapyridine (SASP), which has been in clinical use for over 50 years, was reported by the National Toxicology Program to increase rat (F344 strain) urinary bladder and mouse (B6C3F1 hybrid) liver tumours under ad libitum (AL) feeding conditions, while under a feed restriction (FR) regimen, these tumours were not increased. The present investigations were undertaken to assess the implications of these results for the safety of SASP in humans. SASP and its 2 major metabolites, 5-aminosalicylic acid (ASA) and sulfapyridine (SP) were tested for in vivo induction of micronuclei in mouse bone marrow cells with or without prefolic treatment and for in vivo formation of DNA adducts in rat and mouse liver and urinary bladder. None exhibited mutagenicity or DNA reactivity. SASP and SP have induced sister chromatid exchanges and micronuclei (MN) in cultured human lymphocytes in the absence of liver activation enzymes and in B6C3F1 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 the sensitivity of this species. Thus, SASP without folate supplementation 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 urothelial hyperplasia and papillomas in the urinary bladders of male rats primarily. In the FR high dose SASP group, the hyperplasia was reduced from 82% to 14%. At the end of 2 years, the incidence of multi-organ leukemia was reduced in both AL and FR high dose SASP groups. Thus, SASP caused intraluminal bladder changes in the rat (especially males) consisting of chronic urothelial stimulation, concretions, hyperplasia which resulted in neoplasia. In the mouse, because of species differences in liver ratios (mouse > rat) and, increasing (3 times higher) liver perfusion in the mouse, compared to the rat, there was hepatocellular toxicity and resulting preneoplasia and neoplasia within 2 years. 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 genotoxic. 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 other organs. Accordingly, SASP is judged to pose no carcinogenic risk to humans.
Iatropoulos
M J
MJ
American Health Foundation, New York, USA.
Williams
G M
GM
Abdo
K M
KM
Kari
F W
FW
Hart
R W
RW
D000636:Aminosalicylic Acids / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000633:toxicity; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D015197:Carcinogenicity Tests; D018736:DNA Adducts / Q000187:drug effects; D005260:Female; D005492:Folic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D008297:Male; D019804:Mesalamine; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013427:Sulfapyridine / Q000493:pharmacokinetics / Q000633:toxicity; D012460:Sulfasalazine / Q000493:pharmacokinetics / Q000633:toxicity*; D001743:Urinary Bladder / Q000187:drug effects*
D000636:Aminosalicylic Acids; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D018736:DNA Adducts; D012460:Sulfasalazine; D019804:Mesalamine; D005492:Folic Acid; D013427:Sulfapyridine