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).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Anttila, S., Hukkanen, J., Hakkola, J., Stjemvall, T., Beaune, P., Edwards, R. J., Boobis, A.R., Pelkonen, O., and Raunio, H., 1997, Expression and localization of CYP3A4 and CYP3A5 in human lung. Am. J. Respir. Cell Mol. Biol 16:242–249.
Bolton, J.L., and Thompson, J.A., 1991, Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes, Drug Metabol. Dispos 19:467–472.
Fan, P.W., Zhang, F., and Bolton, J.L., 2000, 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides, Chem. Res. Toxicol 13:45–52.
Forkert, P.-G., and Lee, R.P., 1997, Metabolism of ethyl carbamate by pulmonary cytochrome P450 and carboxylesterase isozymes: Involvement of CYP2E1 and hydrolase A1, Toxicol. Appl. Pharmacol 146:245–254.
Guan, Y., Fisher, M.B., Lang, D.H., Zheng, Y.-M., Koop, D.R., and Rettie, A.E., 1998, Cytochrome P450-dependent desaturation of lauric acid: isoform selectivity and mechanism of formation of 11dodecenoic acid, Chem.-Biot. Inter 110:103–121.
Guengerich, F.P., and Kim, D.-H., 1991, Enzymatic oxidation of ethyl carbamate to vinyl carbamate and its role as an intermediate in the formation of 1,N6-ethenoadenosine, Chem. Res. Toxicol 4:413–421.
Han, D.H., Pearson, P.G., Baillie, T.A., Dayal, R., Tsang, L.H., and Gescher, A., 1990, Chemical synthesis and cytotoxic properties of N-alkylcarbamic acid thioesters, metabolites of hepatotoxic formamides, Chem. Res. Toxicol 3:118–124.
Higgins, L., Bennett, G.A., Shimoji, M., and Jones, J.P., 1998, Evaluation of cytochrome P450 mechanism and kinetics using kinetic deuterium isotope effects, Biochem 37:7039–7046.
Lanza, D.L., Code, E., Crespi, C.L., Gonzalez, F.J., and Yost, G.S., 1999, Specific dehydrogenation of 3methylindole and epoxidation of naphthalene by CYP2F1 expressed in human lymphoblastoid cells. Drug Metab. Dispos 27:798–803.
Lewis, M.A., Yoerg, D.G., Bolton, J.L., and Thompson, J.A., 1996, Alkylation of 2’-deoxynucleosides and DNA by quinone methides derived from 2,6-di-tert-butyl-4-methylphenol, Chem. Res. Toxicol 9:1368–1374.
Mace, K., Bowman, E.D., Vautravers, P., Shields, P.G., Harris, C.C., and Pfeifer, A.M.A., 1998, Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues Eur. J. Cancer 34:914–920.
Nhamburo, P.T., Gonzalez, F.J., McBride, O.W., Gelboin, H.V., and Kimura, S., 1989, Identification of a new P-450 expressed in human lung: Complete cDNA sequence, cDNA-directed expression and chromosome mapping, Biochemistry 28:8060–8066.
Nhamburo P.T., Kimura S., McBride O.W., Kozak C.A., Gelboin H., and Gonzalez F.J., 1990, The human CYP2F gene subfamily: identification of a cDNA encoding a new cytochrome P450, cDNA-directed expression, and chromosome mapping, Biochemistry 29:5491–5499.
Ortiz de Montellano, P.R., 1995, Oxygen activation and reactivity in Cytochrome P450: StructureMechanism and Biochemistry(2 nd Edition, P.R Ortiz de Montellano, ed.) Plenum Press, New York, 245–303.
Pelkonen, O. and Raunio, H., 1997, Metabolic activation of toxins: tissue-specific expression and metabolism in target organs Environ. Health Perspec 105:767–774.
Racha, J.K., Renie, A.E., and Kunze, K.L., 1998, Mechanism-based inactivation of human cytochrome P450 1A2 by furafylline: detection of a 1:1 adduct to protein and evidence for the formation of a novel imidazomethide intermediate, Biochem 37:7407–7419.
Regal, K.A., Laws, G., Yost, G.S., Yuan, C., and Skiles, G.L., 1999, Formation and detection of 3-methylindole DNA adducts ISSX Proceedings 9thNorth American ISSX Meeting, 15:223.
Rettie, A.E., Sheffels, P.R., Korzekwa, K.R., Gonzalez, F.J., Philpot, R.M., and Baillie, T.A., 1995, CYP4 isozyme specificity and the relationship between cu-hydroxylation and terminal desaturation of valproic acid, Biochem 34:7889–7895.
Skiles, G.L., and Yost, G.S., 1996, Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole, Chem. Res. Toxicol 9:291–297.
Skordos, K.W., Laycock, J.D., and Yost, G.S., 1998a, Thioether adducts of a new imine reactive intermediate of the pneumotoxin 3-methylindole, Chem. Res. Toxicol 11:1326–1331.
Skordos, K.W., Skiles, G.L., Laycock, J.D., Lanza, D.L., and Yost, G.S., 1998b, Evidence supporting the formation of 2, 3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole, Chem. Res. Toxicol 11:741–749.
Thornton-Manning, J.R., Appleton, M.L., Gonzalez, F.J. and Yost, G.S., 1996, Metabolism of 3methylindole by vaccinia-expressed P450 enzymes: correlation of 3-methyleneindolenine formation and protein-binding, J. Pharmacol. Exp. Ther 276:21–29.
Wang, H., Lanza, D.L., and Yost, G.S., 1998, Cloning and expression of CYP2F3, a cytochrome P450 that bioactivates the selective pneumotoxins 3-methylindole and naphthalene, Arch. Biochem. Biophys 349:329–340.
Yost, G.S., 1997, Selected, nontherapeutic agents in Comprehensive Toxicology(Sipes, I. G., McQueen, C.A., and Gandolfi, A.J., eds), Vol. 8 Toxicology of the Respiratory System(Roth, R.A., ed.) Elsevier Science, New York, 591–610.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2001 Springer Science+Business Media New York
About this chapter
Cite this chapter
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
Download citation
DOI: https://doi.org/10.1007/978-1-4615-0667-6_6
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5185-6
Online ISBN: 978-1-4615-0667-6
eBook Packages: Springer Book Archive