Decreased pneumotoxicity of deuterated 3-methylindole: Bioactivation requires methyl CH bond breakage

Huijzer, Jeannette C.; Adams, James D.; Yost, Garold S.

doi:10.1016/0041-008x(87)90306-1

Cited by 27 publications

(9 citation statements)

References 22 publications

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“…Extensive studies have shown that dehydrogenation of 3MI to 3-methyleneindolenine represents a major bioactivation route leading to the ultimate pneumotoxicity of the compound (Nocerini et al, 1985a,b;Yost et al, 1986;Huijzer et al, 1987). However, we have recently shown (Yan et al, 2007) that several P450 enzymes catalyzed the formation of at least two novel electrophilic quinoneimines (one putative isomer is illustrated in Scheme 1) that were trapped with GSH and identified by mass spectrometry.…”

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Inactivation of Lung-Selective Cytochrome P450 CYP2F Enzymes

Kartha¹,

Yost²

2007

Drug Metab Dispos

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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 M, 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 M, 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.

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Section: Discussionmentioning

confidence: 99%

Mechanism-Based Inactivation of Lung-Selective Cytochrome P450 CYP2F Enzymes

Kartha¹,

Yost²

2007

Drug Metab Dispos

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“…In terms of the putative active agent, imino methides are known [54], and indeed have been implicated in cytotoxic processes [55][56][57][58][59][60]. However, while acetylated quinone imines are also important toxic metabolites, for example of the Parkinson's disease drug tolcapone [48] and the analgesic acetaminophen [61], acetylated imine methides are rare.…”

Section: Electrochemistrymentioning

confidence: 99%

The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

Pigeon

Top

Zekri

et al. 2009

Journal of Organometallic Chemistry

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a b s t r a c tWe have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via oxidative quinone methide formation. We now present a series of analogous amine and acetamide compounds: 2-ferrocenyl-1-(4-aminophenyl)-1-phenyl-but-1-ene (Z+E-2), 2-ferrocenyl-1-(4-Nacetylaminophenyl)-1-phenyl-but-1-ene (Z-3), and their corresponding organic molecules 1-(4-aminophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-4) and 1-(4-N-acetamidophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-5). All of the compounds have adequate relative binding affinity values for the estrogen receptor; between 2.8% and 5.7% for ERa, and between 0.18% and 15.5% for ERb, as well as exothermic ligand binding in in silico ER docking experiments. Compounds 2 and 3 show dual estrogenic/cytotoxic activity on the MCF-7 cell line; they are proliferative at low concentrations (0.1 lM) and antiproliferative at high concentrations (10 lM). On the MDA-MB-231 cell line, the ferrocenyl complexes 2 and 3 are antiproliferative with IC 50 values of 0.8 lM for 2 and 0.65 lM for 3, while the purely organic molecules 4 and 5 show no effect. Electrochemical experiments suggest that both 2 and 3 can be transformed to oxidized quinoidtype species, analogous to what had previously been observed for the ferrocene phenols.

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“…D3-3MI was synthesized by LiAlD4 reduction of indole-3-carboxylic acid and used to evaluate possible deuterium isotope effects in vivo (22). D3-3MI was found to be considerably less toxic than 3MI in mice.…”

Section: Deuterium Isotope Effects As Mechanistic Probesmentioning

confidence: 99%