Detail Alterations in cytochrome P450 2E1 expression following the acute phase response: Implications of endotoxemia and traumatic brain injury Bibliografi Author: Blouin, Robert A. (Advisor); Poloyac, Samuel Mark Topik: HEALTH SCIENCES; PHARMACOLOGY Bahasa: (EN )    ISBN: 0-599-72834-5     Penerbit: University of Kentucky Press     Tahun Terbit: 1999     Jenis: Theses - Dissertation Fulltext: 9968092.pdf (0.0B; 1 download) Abstract Activation of the acute phase response (APR) underlies the pathogenesis of several diseases and alters the expression of P450 enzymes. CYP2E1 is the ethanol inducible P450 involved in the metabolism of drugs, environmental contaminants, eicosanoids, as well as, free radical production. It is the purpose of this research to evaluate alterations in CYP2E1 expression following the APR in models of both microbial and traumatic insult. The purpose of the first study was to evaluate CYP2E1 expression in LPS (2.0 mg i.p./animal) injected rats. CYP2E1 mediated 6-hydroxychlorzoxazone formation in liver microsomes decreased at 4 through 72 hours with maximal reduction to 50% of control at 48 hours (p < 0.01). CYP2E1 protein was decreased at 24, 48 and 72 hours with a maximal depression to 67% of control at 48 hours (p < 0.05). The second study evaluated alterations in chlorzoxazone (500mg orally) pharmacokinetics in twelve healthy males after 2 LPS doses (20 endotoxin units/kg/day) and after saline administration. LPS did not produce a significant change in chlorzoxazone oral clearance or 6-hydroxychlorzoxazone formation clearance. In contrast, a significant increase in 6-hydroxychlorzoxazone glucuronide renal clearance was observed (LPS; 7.5 ± 1.37 ml/min/kg vs. control; 6.1 ± 1.7 ml/min/kg). The final study of this research evaluated liver, kidney, and brain microsome 6-hydroxychlorzoxazone formation in a traumatic brain injury (TBI) rat model. Rats received anesthesia control, craniotomy, or craniotomy plus TBI and were sacrificed at 24 and 48 hours. Liver 6-hydroxychlorzoxazone formation decreased to 74 ± 18% of control (p < 0.05) at 48 hours. Kidney microsomes demonstrated increased 6-hydroxychlorzoxazone formation (154% of control; p < 0.01) at 24 hours. In the brain cortex the effect of TBI demonstrated no significant changes from control or CX groups. In summary, these studies demonstrate that the APR elicits multiple effects on the processes involved in drug metabolism and excretion. Hepatic alterations following LPS administration, as well as tissue specific changes in CYP2E1 activity following TBI were observed in the rat. CYP2E1 mediated metabolism was not significantly altered following LPS administration in humans; however, this evaluation revealed significant alterations in renal excretion processes during the APR; thereby, demonstrating that the APR elicits multiple organ specific effects on drug elimination. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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