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Although extensively used as a model, the mechanism(s) by which this chemical insult mimics a condition with genetic and environmental links remains an enigma, although formation of protein adducts has been implicated. Monocrotaline (MCT) is non\u2010toxic and must undergo hepatic dehydrogenation to the soft electrophile monocrotaline pyrrole as prerequisite to damaging endothelial cells lining arterioles at remote pulmonary sites. In this report we extend our earlier investigation (<jats:italic>J. Biol. Chem.<\/jats:italic>\u20052000, <jats:italic>275<\/jats:italic>, 29091\u201329099) by examining protein adducts to lower abundance adducts, a p<jats:italic>I<\/jats:italic> range not covered before, and subcellular localization of adduct\u2010forming proteins associated with plasma membranes. Human pulmonary artery endothelial cells were exposed to [<jats:sup>14<\/jats:sup>C]MCT pyrrole (MCTP) and protein targets were identified using 2\u2010DE with IPG\u20054\u201311. Adducted proteins were identified by p<jats:italic>I<\/jats:italic>, apparent molecular weight, and PMF using MALDI\u2010TOF MS. Results of this study show that the majority of adducts form on proteins that contain reactive thiols in a CXXC motif, such as protein disulfide isomerase\u2005A<jats:sub>3<\/jats:sub> (ERp57), protein disulfide isomerase\u2005(PDI), and endothelial PDI. These same proteins were the major adduct\u2010forming proteins associated with the plasma membrane. Other proteins found to be targets were thioredoxin, galectin\u20101, reticulocalbin\u20051 and 3, cytoskeletal tropomyosin, mitochondrial ATP synthase \u03b2\u2010chain, annexin\u2005A2 and cofilin\u20101. For the first time, MCTP adducts were observed on proteins not known to contain cysteine residues. However, known reactive proteins including nucleophosmin did not form detectable adducts, potentially indicating that MCTP did not reach the interior of nucleus to the same extent as other cellular sites. These findings suggest that molecular events underlying MCTP toxicity are initiated at the plasma membrane or readily accessible subcellular regions including the cytosol and membranes of the endoplasmic reticulum and mitochondria.<\/jats:p>","DOI":"10.1002\/pmic.200402022","type":"journal-article","created":{"date-parts":[[2005,10,13]],"date-time":"2005-10-13T07:50:36Z","timestamp":1129189836000},"page":"4398-4413","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Monocrotaline pyrrole targets proteins with and without cysteine residues in the cytosol and membranes of human pulmonary artery endothelial cells"],"prefix":"10.1002","volume":"5","author":[{"given":"Michael\u2005W.","family":"Lam\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.\u2005Daniel","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis\u2005W.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.\u2005J.","family":"Segall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,11,17]]},"reference":[{"key":"e_1_2_1_2_2","first-page":"153","volume":"55","author":"Hislop A.","year":"1974","journal-title":"Br. 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