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KMID : 0617220000110010051
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Duksung Bulletin Phamaceutical Sciences
2000 Volume.11 No. 1 p.51 ~ p.58
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Studies on Synthetic 1,2-Benzothiazine Anti-inflammatory Agents：Pharmacological Effect and the Expression of Xenobiotic-metabolizing Enzymes
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Abstract
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Expression of xenobiotic-metabolizing enzymes can be altered by xenobiotics, which represents changes in the production of reactive metabolic intermediates as well as toxicities in tissues. Metabolic intermediates derived from xenobiotics are considered to produce the reactive oxygen species including drug free radicals and hydroxyl free radicals, which would be ultimately responsible for drug-induced toxicities. The effects of 1,2-benzothiazine anti-inflammatory agents on the expression of xenobiotic-metabolizing enzymes including major cytochrome P450s, microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) were studied in the liver with the aim of providing the part of information on potential production of reactive metabolites and hepatotoxicity by the agents. The synthetic compounds 24, 36 and 39 exhibited anti-inflammatory effects in rats as assessed by the Randall-Selitto method. The anti-inflammatory effect was detected as early as at 30 min after gavaging the agents with the ED50 being noted at 80 ㎎/㎏, which was comparable to that of ibuprofen. Treatment of rats with each compound (100 ㎎/㎏,3d) resulted in no significant induction in the immunochemically-detectable cytochromes P450 1A1/2, P450 2B1/2, P450 2C11 and P450 2E1. Changes in the mEH expression were also minimal, as evidenced by both Western blot and Northern blot analyses. Hepatic GST expression was slightly increased by the agents: GST Ya protein and mRNA expression was 1.5-fold increased after treatment with compounds 24 and 39, whereas GST Yb1/2 and Yc1/2 mRNA levels were elevated 2-to 3-fold. In summary, the effects of the synthetic 1,2-benzothiazines on the expression of major P450, mEH and GST were not significant, providing evidence that methbolic activation of the agents, potential drug interaction and hepatotoxicity would be minimal.
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