Groups of 6 male BALB/c mice were treated twice daily for 4 days with 1000 mg/kg succinylacetone (SA), a heme biosynthesis inhibitor. Liver cytochrome P450 levels were slightly decreased and coumarin hydroxylase activity was increased from 124 ± 35 to 276 ± 37 pmol/mg/min. Renal cytochrome P450 content was decreased by SA treatment. SA had no effect on brain nitric oxide synthase activity.
Administration of lipopolysaccharide (LPS) increased plasma nitrite/nitrate levels, and pretreatment with SA for 72 h partially attenuated this effect. Plasma nitrate levels were 305 ± 67 μmol/l in LPS-injected mice and 116 ± 27 μmol/l in LPS-injected, succinylacetone pretreated mice. These results indicate that succinylacetone treatment interferes with the inducible nitric oxide synthase activity or with its activation pathway.
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References
1.
Lindblad B., Lindstedt S., Steen G.On the enzymic defects in hereditary tyrosinemia. Proc Natl Acad Sci USA1977; 74: 4641-4654.
Wyss P.A., Boynton S., Chu J., Roth K.S.Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia. Biochim Biophys Acta1993; 1182: 323-328.
Hess R.A., Tschudy D.P., Blaese R.M.Immunosuppression by succinylacetone. II. Prevention of graft vs host disease . J Immunol1987; 139: 2845-2849.
6.
Fidler J.M., Chang T.Q., Bauer R., Young J.D., Vitt C.R.Suppression of graft versus host disease by succinylacetone in a rat allogenic bone marrow transplantation model. Transplantation1993; 55: 367-373.
7.
Z Skolik S.A., Palestine A.G., Blaese R.M., Nussenblatt R.B., Hess R.A.Treatment of experimental autoimmune uveitis in the rat with systemic succinylacetone . Clin Immunol Immunopathol1988; 49: 63-71.
8.
Wei X., Charles I.G., Smith A. et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature1995; 375: 408-411.
9.
White K.A., Marletta M.A.Nitric oxide synthase is a cytochrome P-450 type hemoprotein. Biochemistry1992; 31: 6627-6631.
10.
McMillan K. , Bredt D.S., Hirsch D.J., Snyder S.H., Clark J.E., Masters B.S.S.Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide. Proc Natl Acad Sci USA1992; 89: 11141-11145.
11.
Gross S.S., Levi R.Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem1992; 267: 25722-25729.
12.
Bune A.J., Brand M.P., Heales S.J.R., Shergill J.K., Cammack R., Cook H.T.Inhibition of tetrahydrobiopterin synthesis reduces in vivo nitric oxide production in experimental endotoxic shock. Biochem Biophys Res Commun1996; 220: 13-19.
Rutten A.A.J.J.L. , Falke H.E., Catsburg J.F. et al. Interlaboratory comparison of microsomal ethoxyresorufin and pentoxyresorufin O-dealkylation determinations: standardization of assay conditions. Arch Toxicol1992; 66: 237-244.
15.
Salonpää P. , Krause K., Pelkonen O., Raunio H.Up-regulation of CYP2A5 expression by porphyrogenic agents in mouse liver. Naunyn-Schmiedebergs Arch Pharmacol1995; 351: 446-452.
16.
Veszelovszky E., Holford N.H.G., Thomsen L.L., Knowles R.G., Baguley B.C.Plasma nitrate clearance in mice: modelling of the systemic production of nitrate following the induction of nitric oxide synthesis. Cancer Chemother Pharmacol1995 ; 36: 155-159.
17.
Seo H.G., Fujii J., Soejima H., Niikawa N., Taniguchi N.Heme requirement for production of active endothelial nitric oxide synthase in baculovirus-infected insect cells. Biochem Biophys Res Commun1995; 208: 10-18.
18.
Castaneda V.L. , Parmley R.T., Pinnix I.B., Raju S.G., Guzman G.S., Kinkade J.M.Ultrastructural, immunochemical and cytochemical study of myeloperoxidase in myeloid leukemia HL-60 cells following treatment with succinylacetone, an inhibitor of heme biosynthesis. Exp Hematol1992; 20: 916-924.
