![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 29, Issue 7, 950-953, July 2001
Department of Pharmacology 3-Methylindole (3 MI) is a selective pulmonary toxicant, and
cytochrome P450 (P450) bioactivation of 3 MI, through hydroxylation, epoxidation, or dehydrogenation pathways, is a prerequisite for toxicity. CYP2F1 and CYP2F3 exclusively catalyze the dehydrogenation of
3 MI to 3-methyleneindolenine, without detectable formation of the
hydroxylation or epoxidation products. It was not known whether 3 MI is
simply an excellent dehydrogenation substrate for all P450 enzymes, or
whether certain cytochrome P450s responsible for 3 MI bioactivation
have unique active sites that only catalyze the dehydrogenation of the
molecule, while other P450s would catalyze only the oxygenation of 3 MI. Therefore, the kinetics of product formation by the CYP2F1 and
CYP2F3 enzymes were compared with other cytochrome P450 enzymes. The
enzymes tested were CYP1A1, CYP1A2, CYP1B1, and CYP2E1. The CYP1A1 and
CYP1A2 enzymes produced all three 3 MI metabolites: the dehydrogenation
product, 3-methyleneindolenine (Vmax/Km = 4 and 22, respectively); the hydroxylation product, indole-3-carbinol
(Vmax/Km = 42 and 100, respectively); and the epoxidation product,
3-methyloxindole
(Vmax/Km = 4 and 72, respectively). These CYP1A enzymes catalyzed oxygenation of 3 MI at much faster rates than dehydrogenation. CYP1B1 produced
indole-3-carbinol (Vmax/Km = 85) and 3-methyloxindole
(Vmax/Km = 7), and CYP2E1 only produced 3-methyloxindole
(Vmax/Km = 98), but neither enzyme catalyzed the formation of the dehydrogenated
product. Six additional P450 enzymes that were tested formed none of
the dehydrogenation product. The ability of the various CYP1 family
enzymes to catalyze the formation of all three major 3 MI metabolites,
along with the specific oxygenation by CYP2E1, illustrates that
dehydrogenation of 3 MI is not a substrate-directed process, but that
the members of the CYP2F family possess unique active sites that
specifically catalyze only the dehydrogenation mechanism.
and Toxicology,
University of
Utah,
Salt Lake City, Utah
This article has been cited by other articles:
|
|
 |
|
  J. M. Weems, Ned. S. Cutler, C. Moore, W. K. Nichols, D. Martin, E. Makin, J. G. Lamb, and G. S. Yost 3-Methylindole is Mutagenic and a Possible Pulmonary Carcinogen Toxicol. Sci., November 1, 2009; 112(1): 59 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D'Agostino, X. Zhuo, M. Shadid, D. G. Morgan, X. Zhang, W. G. Humphreys, Y.-Z. Shu, G. S. Yost, and X. Ding The Pneumotoxin 3-Methylindole Is a Substrate and a Mechanism-Based Inactivator of CYP2A13, a Human Cytochrome P450 Enzyme Preferentially Expressed in the Respiratory Tract Drug Metab. Dispos., October 1, 2009; 37(10): 2018 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Kartha and G. S. Yost Mechanism-Based Inactivation of Lung-Selective Cytochrome P450 CYP2F Enzymes Drug Metab. Dispos., January 1, 2008; 36(1): 155 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Terner, W. J. Gilmore, Y. Lou, and E. J. Squires THE ROLE OF CYP2A AND CYP2E1 IN THE METABOLISM OF 3-METHYLINDOLE IN PRIMARY CULTURED PORCINE HEPATOCYTES Drug Metab. Dispos., May 1, 2006; 34(5): 848 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wan, B. A. Carr, N. S. Cutler, D. L. Lanza, R. N. Hines, and G. S. Yost SP1 AND SP3 REGULATE BASAL TRANSCRIPTION OF THE HUMAN CYP2F1 GENE Drug Metab. Dispos., August 1, 2005; 33(8): 1244 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Simmonds, C. A. Reilly, R. M. Baldwin, B. I. Ghanayem, D. L. Lanza, G. S. Yost, K. S. Collins, and P.-G. Forkert BIOACTIVATION OF 1,1-DICHLOROETHYLENE TO ITS EPOXIDE BY CYP2E1 AND CYP2F ENZYMES Drug Metab. Dispos., September 1, 2004; 32(9): 1032 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Carr, S. Ramakanth, G. A. Dannan, and G. S. Yost Characterization of Pulmonary CYP4B2, Specific Catalyst of Methyl Oxidation of 3-Methylindole Mol. Pharmacol., May 1, 2003; 63(5): 1137 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Carr, J. Wan, R. N. Hines, and G. S. Yost Characterization of the Human Lung CYP2F1 Gene and Identification of a Novel Lung-specific Binding Motif J. Biol. Chem., April 25, 2003; 278(18): 15473 - 15483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. K. Nichols, R. Mehta, K. Skordos, K. Mace, A. M. A. Pfeifer, B. A. Carr, T. Minko, S. W. Burchiel, and G. S. Yost 3-Methylindole-Induced Toxicity to Human Bronchial Epithelial Cell Lines Toxicol. Sci., February 1, 2003; 71(2): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
