Reszka Krzysztof J, Britigan Laura H, Rasmussen George T, Wagner Brett A, Burns C Patrick, Britigan Bradley E
Research Service, VA Medical Center, Iowa City, IA 52246, USA.
Arch Biochem Biophys. 2004 Jul 1;427(1):16-29. doi: 10.1016/j.abb.2004.04.012.
Acetaminophen, a common analgesic and antipyretic drug, is frequently administered to individuals undergoing anthracycline chemotherapy. Here, the effect of acetaminophen on the metabolism of daunorubicin and doxorubicin by isolated enzymes lactoperoxidase and myeloperoxidase, and by myeloperoxidase-containing human leukemia HL-60 cells was investigated using spectrophotometric and EPR techniques. We report that at pharmacological concentrations acetaminophen strongly stimulates oxidation of the anthracyclines by lactoperoxidase and myeloperoxidase systems, which results in irreversibly altered (colorless) products. The initial rate and efficacy of daunorubicin oxidation depends on pH. While at pH approximately 7 the oxidation is rapid and extensive, almost no oxidation occurs at pH approximately 5. In the absence of daunorubicin, oxidation of acetaminophen by lactoperoxidase/hydrogen peroxide is only weakly dependent on pH, however, at pH 7.4 it strongly depends on [daunorubicin]. Ascorbate and reduced glutathione strongly inhibited oxidation of anthracyclines by lactoperoxidase and HL-60 systems. Using EPR, a daunorubicin-derived radical was detected in a daunorubicin/acetaminophen/peroxidase/hydrogen peroxide system as a narrow single line (0.175 mT) with g = 2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g = 2.0043, line width approximately 0.5 mT). Similar results were obtained with doxorubicin. We suggest that the stimulation by acetaminophen is primarily due to its preferential oxidation by peroxidases to the corresponding phenoxyl radical, which subsequently reacts with daunorubicin (doxorubicin). Because biological properties of oxidatively transformed anthracyclines will certainly be different from those of their parent compounds, the possible acetaminophen-enhanced degradation of the anthracyclines in vivo is likely to interfere with anticancer and/or cardiotoxic activities of these agents.
对乙酰氨基酚是一种常见的止痛和解热药物，常用于接受蒽环类化疗的患者。在此，我们使用分光光度法和电子顺磁共振（EPR）技术，研究了对乙酰氨基酚对分离出的乳过氧化物酶和髓过氧化物酶以及含髓过氧化物酶的人白血病HL-60细胞代谢柔红霉素和阿霉素的影响。我们报告称，在药理浓度下，对乙酰氨基酚强烈刺激乳过氧化物酶和髓过氧化物酶系统对蒽环类药物的氧化作用，这会导致生成不可逆改变的（无色）产物。柔红霉素氧化的初始速率和效率取决于pH值。在pH约为7时，氧化迅速且广泛，而在pH约为5时几乎不发生氧化。在没有柔红霉素的情况下，乳过氧化物酶/过氧化氢对乙酰氨基酚的氧化仅微弱依赖于pH值，然而，在pH 7.4时它强烈依赖于[柔红霉素]。抗坏血酸和还原型谷胱甘肽强烈抑制乳过氧化物酶和HL-
