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A relatively unknown reaction catalyzed by the P450s, but very important for human health, is the activation of halogenated substrates, which may lead to toxicity problems. However, its catalytic mechanism is currently unknown and, therefore, we performed a detailed computational study. To gain insight into the metabolism of halogenated compounds by P450 enzymes, we have investigated the oxidative and reductive P450\u2010mediated activation of tetra\u2010 and trichloromethane as halogenated models with density functional theory (DFT) methods. We propose an oxidative halosylation mechanism for CCl<jats:sub>4<\/jats:sub> under aerobic conditions by Compound\u2005I of P450, which follows the typical Groves\u2010type rebound mechanism. By contrast, the metabolism of CHCl<jats:sub>3<\/jats:sub> occurs preferentially via an initial hydrogen\u2010atom abstraction rather than halosylation. Kinetic isotope effect studies should, therefore, be able to distinguish the mechanistic pathways of CCl<jats:sub>4<\/jats:sub> versus CHCl<jats:sub>3<\/jats:sub>. We find a novel mechanism that is different from the well accepted P450 substrate activation mechanisms reported previously. Moreover, the studies highlight the substrate specific activation pathways by P450 enzymes leading to different products. These reactivity differences are rationalized using Marcus theory equations, which reproduce experimental product distributions.<\/jats:p>","DOI":"10.1002\/asia.201301608","type":"journal-article","created":{"date-parts":[[2014,2,5]],"date-time":"2014-02-05T14:36:07Z","timestamp":1391610967000},"page":"1175-1182","source":"Crossref","is-referenced-by-count":27,"title":["Metabolism of Halogenated Alkanes by Cytochrome P450 enzymes. Aerobic Oxidation versus Anaerobic Reduction"],"prefix":"10.1002","volume":"9","author":[{"given":"Li","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam P.","family":"de\u2005Visser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,2,5]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/es00162a001"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/713611034"},{"key":"e_1_2_6_3_2","unstructured":"\u00a0"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(00)00149-6"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.31.3.266"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2007.10.014"},{"key":"e_1_2_6_7_2","unstructured":"\u00a0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9500500"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0830019100"},{"key":"e_1_2_6_10_2","volume-title":"Cytochrome P450: Structure, Mechanism, and Biochemistry, 3rd\u2005ed.","author":"Ortiz de Montellano P. 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