Effect ob broad-spectrum antibiotics on in vitro synthesis of DNA in the rabbit colon.
Rabbit colonic mucosa was cultured in vitro in the presence of broad-spectrum antibiotics. DNA synthesis, as determined by [3H]thymidine incorporation into DNA, was inhibited by clindamycin (32%) and tetracycline (28%). Penicillin G, ampicillin, and metronidazole had no effect. When bile acids were added to the incubation at a concentration of 10 mM, the more lipophilic drug, lincomycin, inhibited DNA synthesis by 38% (cholic acid) and by 23% (chenic acid). Bile acids alone did not alter thymidine incorporation. Inhibition by clindamycin demonstrated a gradual dose-response curve, with inhibition first noted at about 20 microgram of antibiotic/ml and maximal inhibition at 1,000 microgram/ml. The more biologically active metabolite of clindamycin, N-demethylclindamycin, inhibited DNA synthesis at concentrations of as low as 10 microgram/ml. The inhibition was reversible, and the drugs did not affect thymidine uptake, thymidine pool concentrations, or protein or mucopolysaccharide synthesis at concentrations of up to 300 microgram/ml. These data demonstrate a direct but reversible toxic action on mammalian colonic mucosa by certain antibiotics implicated in the production of pseudomembranous colitis and are consistent with the hypothesis that such a toxic action may be one factor in the pathogenesis of antibiotic-associated colitis.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002981:Clindamycin / Q000494:pharmacology; D003106:Colon; D004247:DNA / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008034:Lincomycin / Q000494:pharmacology; D011817:Rabbits; D013752:Tetracycline / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002981:Clindamycin; D004247:DNA; D008034:Lincomycin; D013752:Tetracycline