Effect of inflammation on the rabbit hepatic cytochrome P-450 isoenzymes: alterations in the kinetics and dynamics of tolbutamide.
In order to determine the effect of inflammation on the kinetics and dynamics of tolbutamide, two groups of seven and nine New Zealand rabbits received 50 mg/kg tolbutamide before and 48 hr after the production of an inflammatory reaction generated by the s.c. administration of turpentine in both hind legs. Tolbutamide in plasma and its two major metabolites (hydroxytolbutamide) and carboxytolbutamide in urine were assayed by high-performance liquid chromatography. The influence of inflammation on hepatic cytochrome P-450 was assessed by 1) determining the hepatic concentration in cytochrome P-450 and b5, 2) characterizing the activity of tolbutamide hydroxylase, 3) isolating hepatic microsomal protein bands by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 4) measuring the concentrations of hepatic cytochrome P-450 isozymes LM-2 and LM-3c. The inflammatory reaction induced a marked decrease in tolbutamide total body clearance, secondary to a reduction in its metabolic clearance. Concerning the metabolites, hydroxytolbutamide metabolic rate constant and the fraction of the dose recovered in urine as carboxytolbutamide were diminished. Tolbutamide hypoglycemic response was not significantly affected by the inflammatory process. The Vmax of tolbutamide hydroxylase was reduced from 14.6 +/- 2.3 to 5.6 +/- 1.4 nmol/mg/60 min (P less than .05), and the Km remained unchanged. The concentration of hepatic cytochrome P-450 was reduced in turpentine-treated rabbits, whereas the cytochrome b5 concentration remained the same in both groups. The systemic inflammation also reduced the content in the 48, 52, 54 and 60 kDa protein bands from hepatic microsomes and the concentration of the LM-3c form.(ABSTRACT TRUNCATED AT 250 WORDS)
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Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Ste-Foy, Québec, Canada.
Bélanger
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Jutras
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du Souich
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D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007003:Hypoglycemia / Q000139:chemically induced; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009961:Orosomucoid / Q000378:metabolism; D011817:Rabbits; D014044:Tolbutamide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014425:Turpentine / Q000633:toxicity
D007527:Isoenzymes; D009961:Orosomucoid; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D014425:Turpentine