化学反応性に起因する薬物毒性メカニズムの多様性 [in Japanese] Diversity in Chemical Mechanisms Involved in Drug Toxicity Caused by Chemically Reactive Species [in Japanese]
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A large number of electrophilic reactive metabolites, such as quinone derivatives, Michael acceptors, nitrogen-containing electrophiles, and epoxides, are produced from drug candidates by drug-metabolizing enzymes, mainly cytochrome P450s. However, reactive metabolites are very unstable and can only be detected after being trapped by nucleophiles. Glutathione and its derivatives are the most utilized nucleophilic trapping reagents. Glutathione-trapped reactive metabolites can be detected by various methods using liquid chromatography-mass spectrometry. Moreover, some drug compounds are naturally chemically reactive to a certain extent. These include β-lactam antibiotics and sulfhydryl-containing drugs. Our study on rofecoxib, a cyclooxygenase-2 inhibitor withdrawn from the market in 2004, suggests that it is a nucleophilic reactive drug that reacts with the aldehyde group of allysine, thereby preventing the formation of cross-linkages in elastin and causing degradation of the elastic fibers in the aorta.
- J. Mass Spectrom. Soc. Jpn.
J. Mass Spectrom. Soc. Jpn. 56(3), 151-154, 2008-06-01
The Mass Spectrometry Society of Japan