Immunostimulating lipopeptide, LtriP (RP 56142): comparison of the effect on hepatic cytochrome P 450 modulation and radioprotection in male and female of three mouse strains.
The sex-dependent effect of lauroyl-L-Ala-D-gamma-Glu-L,L-A2pmNH2 (LtriP, RP 56142) on hepatic microsomal cytochromes P 450 (cyt P 450) was studied in three mouse strains NMRI, C3H/OuJ and C3H/HeJ. In NMRI and C3H/OuJ, strains which are responsive to bacterial lipopolysaccharides (LPS-responsive), regardless of the sex of the mouse, significant decrease in the amount of cyt P 450 was observed after LtriP treatment, with a concomitant reduction in ethoxyresorufin-O-deethylase (cyt P 450 1A-dependent) and 7-ethoxycoumarin-O-deethylase activities. This was not seen in C3H/HeJ (LPS-hyporesponsive) mice. These effects may be related to LtriP-dependent cytokine induction, since neither LtriP nor LPS stimulated interleukin-1 (IL-1) secretion by C3H/HeJ macrophages. 11- and 12-hydroxylations (11- and 12-OH) of lauric acid were compared in C3H/OuJ and C3H/HeJ mice. LtriP depressed the total enzymatic conversion of lauric acid in the two strains without modification of the 11/12-OH ratio for C3H/OuJ or male C3H/HeJ mice. However, in females C3H/HeJ mice this decrease was particularly significant and concerned especially the 12-OH activity (a marker of cyt P450 4A family). Although males of the three strains were more sensitive to irradiation than females, LtriP exerted a sex-independent radioprotection on NMRI and C3H/OuJ mice. Its radioprotective effect was illustrated by the preservation of all the enzymatic activities studied in treated NMRI mice, contrary to irradiated control animals. In contrast, for the C3H/HeJ strain, males were not protected by LtriP treatment and, furthermore, females showed a marked sensitization to irradiation. The effects in CH3/HeJ strain implicate LtriP in the control of cyt P 450 induction and of sensitivity to irradiation independently of IL-1 induction.
Sedqi
M
M
Laboratoire des protéines, CNRS URA 1188, Université de Paris V, France.
Delaforge
M
M
Mansuy
D
D
Martin
B
B
Jollès
P
P
Migliore-Samour
D
D
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010867:Pimelic Acids / Q000494:pharmacology*; D011837:Radiation-Protective Agents; D012737:Sex Factors
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010867:Pimelic Acids; D011837:Radiation-Protective Agents; C024768:trimexautide; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase