期刊
FASEB JOURNAL
卷 19, 期 2, 页码 635-+出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.04-2437fje
关键词
cyclooxygenase-2; nonsteroidal anti-inflammatory drugs; rofecoxib; lipid peroxide
Acetaminophen is one of the most commonly used drugs for the safe and effective treatment of pain and fever. Acetaminophen works by lowering cyclo-oxygenase products preferentially in the central nervous system, where oxidant stress is strictly limited. However, the precise mechanism of action for acetaminophen on cyclo-oxygenase activity is debated. Two theories prevail. First, it is suggested that acetaminophen selectively inhibits a distinct form of cyclooxygenase, cyclo-oxygenase-3. Second, it is suggested that acetaminophen has no affinity for the active site of cyclo-oxygenase but instead blocks activity by reducing the active oxidized form of cyclo-oxygenase to an inactive form. Here, we have used an in vitro model of cyclo-oxygenase-2 activity (A549 cells stimulated with IL-1 beta) to show that acetaminophen is an effective inhibitor of cyclo-oxygenase activity in intact cells. However, acetaminophen, unlike nonsteroidal antiinflammatory drugs ( NSAIDs), cannot inhibit activity in broken cell preparations. The inhibitory effects of acetaminophen were abolished by increasing intracellular oxidation conditions with the cell-permeable hydroperoxide t-butylOOH. Similarly the inhibitory effects of the cyclooxygenase-2 selective inhibitor rofecoxib or the mixed cyclo-oxygenase-1/cyclo-oxygenase-2 inhibitors ibuprofen and naproxen were significant reduced by t-butylOOH. By contrast, the inhibitory effects of indomethacin or diclofenac, which also inhibit both cyclo- oxygenase-1 and cyclo- oxygenase-2, were unaffected by t-butylOOH. These observations dispel the notion that cyclo- oxygenase-3 is involved in the actions of acetaminophen and provide evidence that supports the theory that acetaminophen interferes with the oxidation state of cyclo- oxygease. Moreover, they suggest for the first time that the inhibitory effects of some NSAIDs, including the newly introduced cyclo- oxygenase-2 selective inhibitor rofecoxib, owe part of their inhibitory actions to effects on oxidation state of cyclo- oxygenase. Our data with t-butylOOH and NSAIDs illustrates an, as yet, undeveloped therapeutic window for the cyclo-oxygenase inhibitor. Specifically, combining active site selectively with actions on enzyme oxidation state would allow for a broader range of tissue selective drugs.
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