Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity

Boekelheide, Kim; Anthony, Douglas C.; Giangaspero, Felice; Gottfried, Marcia R.; Graham, Doyle G.

doi:10.1021/tx00004a002

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…However, recoveries of the Lys-AFB 1 adduct from albumin have been reported to be less than quantitative due to instability ( , ). Bifurcation between pyrroles and lactams has been studied with other bis-carbonyl electrophiles and protein Lys groups in work with 2,5-hexanedione ( , ) and levuglandins ().…”

Section: Discussionmentioning

confidence: 99%

Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine

Guengerich

Voehler

Williams

et al. 2002

Chem. Res. Toxicol.

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Amine conjugates of activated aflatoxin (AF) B(1) are formed in various systems, e.g., buffer amines and with protein lysine groups. Structures have been published in the literature, but the evidence is indirect in that (i) halogenated AFB(1) was usually used as the precursor and (ii) the assignment of the structure of the five-membered ring formed by cyclization is based on NMR chemical shifts. To better define these adducts and distinguish among several possibilities, we synthesized AFB(1) dialdehyde and reacted this with the surrogate methylamine at neutral pH, to simplify the system. The isolated product had the expected molecular ion (mass spectrometry) and showed pH-dependent UV spectra similar to those published for a lysine conjugate. Nuclear Overhauser enhanced spectroscopy (two-dimensional NMR, 800 MHz) of the sample (2H(2)O) showed proximity of the N-CH(3) protons only with a singlet at delta 4.10, assigned to the methylene of the added five-membered ring, but not to a delta 6.53 singlet assigned as the vinylic proton of that ring. All protons in the coumarin-furanone portion of the system were correlated to each other but not to those in the added five-membered ring. These experiments establish the structure as 2,3-dihydro-2-oxo-4-(1,2,3,4-tetrahydro-7-hydroxy-9-methoxy-3,4-dioxocyclopenta[c][1]benzopyran-6-yl)-1H-pyrrole-1-methane. The similarity of the reaction to that occurring in the reaction of AFB(1) dialdehyde with lysine and the agreement of the UV spectra suggest that this structure is applicable for the lysine analogue. The NMR results support the possible structure B of Sabbioni et al. [Sabbioni, G., Skipper, P. L., Buchi, G., and Tannenbaum, S. R. (1987) Carcinogenesis 8, 819-824] and the proposed structure 8 of Sabbioni [Sabbioni, G. (1990) Chem.-Biol. Interact. 75, 1-15] but not alternative proposals. Kinetic and mechanistic considerations of the reaction of lysine with AFB(1) dialdehyde are presented in the previous article in this issue [Guengerich, F. P., Arneson, K. O., Williams, K. M., Deng, Z., and Harris, T. M. (2002) Chem. Res. Toxicol. 15, 780-793].

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Section: Discussionmentioning

confidence: 99%

Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine

Guengerich

Voehler

Williams

et al. 2002

Chem. Res. Toxicol.

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“…A unique feature of 2,5-HD is the several-week-long latency period between the initiation of exposure and the onset of pathology (Boekelheide, 1988). The mechanism of delayed toxicity may be due to sequential steps of pyrrole formation, oxidation, and crosslinking that are necessary events in the pathogenesis of 2,5-HD-induced testicular injury (Genter et al, 1987;Boekelheide et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Effects of Sertoli Cell Toxicants 2,5-Hexanedione, Carbendazim, and Mono-(2-ethylhexyl) phthalate in Adult Rat Testis

et al. 2007

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Sertoli cells are the primary cellular target for a number of pharmaceutical and environmental testicular toxicants, including 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate. Exposure to these individual compounds can result in impaired Sertoli cell function and subsequent germ cell loss. The loss of testicular function is marked by histopathological changes in seminiferous tubule diameter, seminiferous epithelial sloughing, vacuolization, spermatid head retention, germ cell apoptosis, and altered microtubule assembly. The present study investigates dose-response relationships for these classic Sertoli cell toxicants using histopathology endpoints. Understanding the relationship between the Sertoli cell toxicant dose and its histopathologic manifestations will help establish the sensitivity of these endpoints as markers of testicular injury. The results indicate that no single histopathology endpoint was sensitive on its own in identifying altered testicular morphology resulting from toxicant exposure. However, when multiple endpoints were combined dose-response relationships could be associated with incremental alterations in histopathology. The data generated from these experiments will be useful in further investigating the effects of Sertoli cell toxicant exposure in animal toxicity studies. In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally.

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“…mon interests in cytochrome P450 [12], which we both continue. In 1995, Professor Doyle G. Graham joined us as Chairman of the Department of Pathology, coming from Duke University where he had developed a reputation in neurotoxicology [13]. Doyle Graham's recruitment to Pathology gave the Center a new presence there, which had not been the case previously.…”

Section: -1998: Further Developmentmentioning

confidence: 99%

The Vanderbilt University Center in Molecular Toxicology: The First 30 Years

Guengerich

1999

Drug Metabolism Reviews

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Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity

Cited by 10 publications

References 19 publications

Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine

Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine

Dose-Dependent Effects of Sertoli Cell Toxicants 2,5-Hexanedione, Carbendazim, and Mono-(2-ethylhexyl) phthalate in Adult Rat Testis

The Vanderbilt University Center in Molecular Toxicology: The First 30 Years

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Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity

Cited by 10 publications

References 19 publications

Structure of the Aflatoxin B1 Dialdehyde Adduct Formed from Reaction with Methylamine

Structure of the Aflatoxin B1 Dialdehyde Adduct Formed from Reaction with Methylamine

Dose-Dependent Effects of Sertoli Cell Toxicants 2,5-Hexanedione, Carbendazim, and Mono-(2-ethylhexyl) phthalate in Adult Rat Testis

The Vanderbilt University Center in Molecular Toxicology: The First 30 Years

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Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine

Structure of the Aflatoxin B₁ Dialdehyde Adduct Formed from Reaction with Methylamine