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Abstract
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INTRODUCTION: P450 metabolism is decreased during sepsis-induced MOF. It is unknown whether this decrease in P4SO enzyme activity is protective or deleterious in MOF. We hypothesized that the P450 suicide inhibitor ABT would sensitize rats to zymosan-induced MOF.
METHODS: Osmotic minipumps were implanted subcutaneousty, infusing either vehicle (40% dimethylsulfoxidc) or ABT (7.8 mg/100g body weight/24 hr). Sprague Dawley rats were further randomized to IP injection of saline or a sublethal dose of zymosan (20 mg/100 g body weight). The four groups studied were vehicle (VEH; n-11), ABT (ABT; n-11), zymosan (ZYM; n=l 1), ABT + ZYM ( n=12). Urinary nitrite/nitrates (UNOx) were collected for a period of 24 hr on day seven, and rats were sacrificed for measure of organ weights and P450 content on day eight Results: All rats in the VEH, ABT, and ZYM groups survived; only 5/12 rats in the ABT + ZYM group survived (Chi square, p<0.001). Mean ±SEM. VEH ABT ZYM ABT+ZYM P450 (nm/g liver) 8664±869 476± 96 7151Ü158 630±630 Liver (g/100g) 3.25±.18 3.84±.10 3.61±.14 5.13±.39 Lung(g/100g) 0.2Ü.01 0.24±.01 0.23±.01 0.36±.04 UNOx (nm/100g/24 h) 28.3±2.1 32.7±3.1 185±45 197± 51 ABT reduced P450 content (ABT: pO.OOl, ZYM: p=0.454, ABTxZYM: p=0.361) and increased zymosan-induced increased liver weight (ABT: pO.OOl, ZYM: pO.OOl, ABTxZYM: p=0.019) and lung weight (ABT: pO.OOl, ZYM: p<0.001, ABTxZYM: p=0.002), without affecting the zymosan-induced increase in UNOx (ABT: p=0.798, ZYM: p<0.001, ABTxZYM: p=0.907)[2 F-ANOVA] Conclusions: Inhibition of P450 increased organ weight and mortality without any further increase in nitric oxide production. This suggests that P450 inhibition increased sensitivity to inflammation P450 enzymes may provide endogenous protection against inflammation-induced multiple organ failure.3M01RR0056.
Language: en |