In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity.
Immunomodulating lipopeptides lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl4-induced lipid peroxidation. In contrast lauroyl-L-Ala-gamma-D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl4-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.
Laboratoire des Protéines, UA 1188 CNRS affiliée à l'INSERM, Université de Paris V, France.
D
D
Migliore-Samour
M
M
Delaforge
M
M
Jaouen
D
D
Mansuy
P
P
Jollès
D000082:Acetaminophen / Q000633:toxicity*; D000276:Adjuvants, Immunologic; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008107:Liver Diseases / Q000517:prevention & control; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010867:Pimelic Acids / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D003573:Cytochrome b Group; D009842:Oligopeptides; D010867:Pimelic Acids; C024768:trimexautide; D000082:Acetaminophen; D009249:NADP; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; C061086:pimelautide