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Drug-Target Interaction

Drug

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PubChem ID:6736
Structure:
Synonyms:
.beta.-Methylindole
1H-Indole, 3-methyl-
3 Methylindole
3-Methyl-1H-indole
3-methyl-2,3-dihydro-1H-indole
3-Methyl-4,5-benzopyrrole
3-Methylindole
3-methylindoline
3-MI
83-34-1
AC-13010
AC1L1N6V
AC1Q1HQS
AG-H-32790
AI3-24372
AP-065/40182778
AR-1F4491
beta-Methylindole
bmse000516
C08313
CCRIS 8961
CHEBI:9171
D012862
EINECS 201-471-7
FEMA No. 3019
HMS2233B05
HSDB 3511
I01-2935
Indole, 3-methyl-
LS-3093
LS-83248
M-3898
M0347
M51458_ALDRICH
methyl-3-indole
MLS001332537
MLS001332538
MolPort-001-759-337
NCGC00167540-01
nchembio.512-comp6
NSC 122024
NSC122024
SBB055975
Scatole
Skatol
Skatole
SMR000677925
STK033388
TL8005477
W301906_ALDRICH
WLN: T56 BMJ D1
ZINC00897468

Target

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Uniprot ID:CP1A1_HUMAN
Synonyms:
CYPIA1
Cytochrome P450 1A1
P450 form 6
P450-C
P450-P1
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

17962375
Mechanism-based inactivation of lung-selective cytochrome P450 CYP2F enzymes.. Jaya S Kartha; Garold S Yost (2008) Drug metabolism and disposition: the biological fate of chemicals display abstract
3-Methylindole (3MI) is a pneumotoxin that requires P450-catalyzed metabolic activation (dehydrogenation), to an electrophilic methylene imine to elicit toxicity. Previous studies have shown that the human pulmonary cytochrome P450 enzyme, CYP2F1, and its goat analog, CYP2F3, catalyzed the dehydrogenation of 3MI. However, it was not known whether the dehydrogenation product could bind to active site nucleophilic residues to inactivate these enzymes. Therefore, the purpose of this study was to determine whether 3MI is a mechanism-based inhibitor of CYP2F3 and CYP2F1. The results showed that both enzymes were highly susceptible to 3MI-mediated suicide inactivation. The k(inact) and the K(I) for CYP2F3 were 0.09/min and 160 microM, respectively, and the approximate partition ratio was 220. Although CYP2F3 lost approximately 80% of its activity in 30 min, a concurrent loss of its reduced carbon monoxide complex was not observed, suggesting that the heme was not destroyed/modified during the inactivation. The exogenous nucleophile, glutathione, did not protect CYP2F1 from 3MI-mediated inactivation, suggesting that the reactive intermediate did not diffuse from the active site before inactivation events. Dialysis of 3MI-inactivated CYP2F3 did not restore activity, and alternate substrates protected CYP2F3. In addition, 3MI inhibited the 7-ethoxycoumarin deethylase activity of human CYP2F1 in a time- and concentration-dependent manner; the k(inact) and K(I) were 0.025/min and 49 microM, respectively. In conclusion, this study presents evidence that 3MI is a mechanism-based inhibitor of both CYP2F3 and CYP2F1, which are important enzymes in the bioactivation of pneumotoxicants such as 3MI or 1,1-dichloroethylene or carcinogens such as naphthalene, benzene, and styrene.