Abstract
Normal cytochrome P450-mediated metabolism of toxicants proceeds through an electron or hydrogen atom abstraction mechanism that generally produces hydroxyl radical equivalents bound to prosthetic heme iron and eventually leads to oxygenated products through a hydroxyl rebound mechanism (Ortiz de Montellano, 1995). In a growing number of examples, certain P450 enzymes initiate oxidation of toxicants through the first step of one-electron abstraction (or hydrogen atom abstraction), but subsequently catalyze a second-electron oxidation that leads to dehydrogenated (desaturated) products. Many of these products are highly reactive electrophiles that initiate toxicities through binding to proteins and/or DNA (Yost, 1997; Guengerich and Kim, 1991; Lewis et al. 1996; Han et al. 1990). The precise chemical environments of the active sites of the enzymes that direct selective dehydrogenation, rather than hydroxylation, are not known. Several of the enzymes that catalyze dehydrogenation of toxicants are selectively expressed in respiratory tissues (Pelkonen and Raunio, 1997; Mace et al. 1998), and much of our work (Thornton-Manning et al. 1996; Lanza et al. 1999) has addressed the mechanisms of dehydrogenation by several human lung-expressed enzymes such as CYP2F1 (Nhamburo et al. 1990) and CYP4B1 (Nhamburo et al. 1989).
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Yost, G.S. (2001). Bioactivation of Toxicants by Cytochrome P450-Mediated Dehydrogenation Mechanisms. In: Dansette, P.M., et al. Biological Reactive Intermediates VI. Advances in Experimental Medicine and Biology, vol 500. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0667-6_6
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DOI: https://doi.org/10.1007/978-1-4615-0667-6_6
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