The Reduction of Nitrobenzoic Acids in the Rat

Publisher Website
Google Scholar
Abstract
1. 4-Nitrobenzoic acid was excreted in rat urine as 4-aminobenzoic acid and its conjugates after oral (20% dose) and intraperitoneal (17% dose) administration. Suppression of gut microflora by oral administration of antibiotics decreased the reduction in vivo (5% dose was reduced after high dose antibiotics and 13% after low dose antibiotics). The liver, intestinal wall and content of the caecum and colon reduced 4-nitrobenzoic acid extensively in vitro. Pre-treatment with antibiotics decreased the activities of intestinal wall and hind gut contents but not of liver. 2. 3-Nitrobenzoic acid was excreted in rat urine as 3-aminobenzoic acid and its conjugates after oral administration to normal (16% dose) and low dose antibiotic-treated animals (7% dose). 2-Nitrobenzoic acid underwent less reduction in vivo in normal animals (10% dose) and this was largely suppressed by low dose antibiotic treatment (1% of dose). The abilities of liver, intestinal wall and caecum and colon contents to reduce 3-nitrobenzoic acid were as great as for the 4-isomer, whereas the host tissues showed decreased ability to reduce 2-nitrobenzoic acid. 3. 4-Nitro[14C]benzoic acid was rapidly eliminated in the urine after oral and i.p. administration to normal rats (94 and 83% dose in 24 h), and oral administration to germ-free rats (84% in 24 h). Faeces contained significant 14C(1-8% dose) in all three groups. Urinary metabolites after oral and i.p. administration to normal rats, and oral administration to germ-free rats, were 4-aminobenzoic acid (2, 1 and 0·6% of urinary 14C respectively), 4-acetamidobenzoic acid (19, 15 and 1% respectively), other metabolites (about 25%) and unchanged compound (55, 63 and 69% respectively). 4. Tissue distribution of 14C after i.p. administration of 4-nitro[14C]benzoic acid showed significant quantities in caecum and colon contents 4 h after dosing, at which time urine contained large amounts of 4-acetamido[14C]benzoic acid. After intra-caecal injection, little urinary 14C was excreted as unchanged compound (5%) or 4-aminobenzoic acid (1%) and most 14C was present as 4-acetamidobenzoic acid (46%) and a polar metabolite (42%). Passage of 4-nitro[14C]benzoic acid from the serosal to mucosal surface of inverted intestinal sacs was inhibited by cyanide. 5. These data confirm that the gut flora is the major site of reduction of 4-nitrobenzoic acid in the rat in vivo and suggest that the compound reached the gut organisms by passage across the intestinal wall possibly by active transport. The product of microbial reduction was well absorbed from caecum and colon, and eliminated in the urine largely as 4-acetamidobenzoic acid. Artefactual reduction of 4-nitrobenzoic acid in urine was not significant.