Uetrecht J
University of Cincinnati, Ohio.
Crit Rev Toxicol. 1990;20(4):213-35. doi: 10.3109/10408449009089863.
This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
本综述提出了一个统一的假说，该假说建立了与几种药物相关的几种超敏反应类型之间的联系，并解释了这些相同药物的一些治疗作用（抗炎活性和抗甲状腺作用）。这个假说的核心是这些药物被过氧化物酶氧化成化学反应性代谢物。所关注的药物具有易于氧化的官能团。参与这个假说的主要过氧化物酶是髓过氧化物酶（MPO），因为它在白细胞中的关键位置，而白细胞在免疫系统功能中起关键作用。然而，甲状腺过氧化物酶可能也能将许多相同的药物氧化成反应性代谢物，这可能是与某些超敏反应相关的甲状腺自身免疫的原因。过氧化物酶也在皮肤和血小板中被描述过，它们的存在可能分别是超敏反应中皮肤反应高发和免疫介导的血小板减少症发生的原因。其他过氧化物酶，如前列腺素过氧化物酶的参与，对药物的抗炎作用可能也很重要。此外，白细胞含有前列腺素合成酶，白细胞的激活会导致花生四烯酸的释放和前列腺素的产生。这个过程也可能导致药物代谢为反应性代谢物。在普鲁卡因胺和氨苯砜代谢的研究中，阿司匹林和吲哚美辛并未抑制中性粒细胞和单核白细胞形成羟胺。这是反对前列腺素合成酶参与这些氧化反应的证据；然而，对其他药物的初步研究表明，前列腺素合成酶可能有助于白细胞对某些药物的代谢。此外，保泰松、苯妥英和替诺昔康的代谢，以及我们对卡马西平等其他药物的初步研究表明，被过氧化物酶代谢为反应性代谢物的药物范围可能比最初怀疑的更广。还有其他几种药物不符合本综述所涵盖的官能团类别，但具有相似的性质。一个很好的例子是α-甲基多巴，它与药物性狼疮、免疫介导的溶血性贫血和其他超敏反应有关。这类药物也可能被过氧化物酶代谢为反应性代谢物。该假说的另一个方面是，感染或其他炎症状态可能是超敏反应的一个重要危险因素，因为这样的刺激会导致白细胞激活，进而导致某些药物形成反应性代谢物。（摘要截选至400字）
