Carbon tetrachloride hepatotoxicity in endotoxin tolerant and polymyxin B-treated rats

Gut-derived endotoxin has been implicated in the hepatotoxic effects of CCl4. The present study has investigated whether two procedures known to block LPS effects would alter the action of CCl4 to decrease hepatic cytochrome P-450 and microsomal drug-metabolizing activity. Administration of polymyxin B or induction of LPS tolerance were shown to attenuate the effect of CCl4 administration to increase SGOT and SGPT levels, signs of hepatic damage. Polymyxin B administration but not LPS tolerance caused a slight decrease in cytochrome P-450. In pretreated animals given CCl4, only those which had received polymyxin B showed a reduced effect of CCl4 to alter cytochrome P-450 level and activity. However, the apparent protective effect was of the same magnitude as the loss of cytochrome P-450 caused by polymyxin B itself. These results suggest that the ability of polymyxin B to ablate the CCl4 loss of P-450 might be due to a reduced metabolic activation of CCl4 by P-450 and not due to any anti-LPS activity. The results suggest that gut-derived LPS does not participate in the effect of CCl4 decreasing cytochrome P-450-mediated reactions. However, participation of LPS in other hepatotoxic effects of CCl4 is not excluded.