The role of microbial flora in the hepatotoxicity of chlortetracycline in vivo: A study with germfree mice

Abstract

Studies with germfree mice have revealed that chlortetracycline (CTC) hepatotoxicity does not depend on secondary effects related to modification of the indigenous microflora but that it is the consequence of a direct drug action. Germfree (GF) and conventionalized (CONV) mice, injected intraperitoneally with large doses of CTC, both developed signs of hepatotoxicity: liver weight, total lipids, and lipid fractions (glycerides, cholesterol, phospholipids) increased, while liver water and protein decreased; activity of the liver enzymes (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, glutamic dehydrogenase, urea cleavage enzyme, and arginase) all decreased, even below that of liver protein concentration. In general, the effect of CTC on the GF mouse was more severe than on the CONV: lipids rose higher, while protein fell lower. In each type of mouse, the concentration of liver glycerides increased most. Fasting exacerbated all these effects especially in the CONV mouse. There were no significant differences between the livers of GF and CONV untreated mice in any of the parameters measured, except for total lipids and glycerides, which were lower in the GF liver. Thus, the presence of an indigenous flora appears not only to attenuate the lipogenic response of the liver to CTC but also to influence the liver lipi composition of the untreated mouse. Our results are consistent with the hypothesis that CTC interferes with protein metabolism of the liver in at least two broad ways: by exerting a catabolic or antianabolic affect, in that liver protein, in general, is decreased after CTC; and by interfering with metalloenzyme action by chelation with metal cofactors, leaving those enzymes relatively unaffected which require no metal cofactors.