Synthesis and 32P-Postlabeling/High-Performance Liquid Chromatography Separation of Diastereomeric 1,N2-(1,3-Propano)-2‘-deoxyguanosine 3‘-Phosphate Adducts Formed from 4-Hydroxy-2-nonenal

Yi, Ping; Zhan, Daqian; Samokyszyn, Victor M.; Doerge, Daniel R.; Fu, Peter P.

doi:10.1021/tx970100r

Cited by 55 publications

(66 citation statements)

References 35 publications

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“…Our results suggest that the 4R-HNE and the 4S-HNE would give roughly equal frequencies of point mutations if each diastereomeric adduct were formed equally. The reaction of racemic HNE with calf thymus DNA and analysis of the adducts by 32 P-postlabeling has been reported [Yi et al, 1997]. Interestingly, only two of the four possible stereoisomers were observed, with (6S, 8R, 11S)-HNE and (6R, 8S, 11R)-HNE being the major product and minor product, respectively.…”

Section: Discussionmentioning

confidence: 97%

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

Fernandes

Wang

Rizzo

et al. 2003

Environ and Mol Mutagen

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Trans-4-hydroxynonenal (HNE) is a toxic compound produced endogenously during lipid peroxidation. HNE is a potent electrophile that is reactive with both proteins and nucleic acids. HNE preferentially reacts with deoxyguanosine to form four stereoisomeric HNE-deoxyguanosine (HNE-dG) adducts: (6R, 8S, 11R), (6S, 8R, 11S), (6R, 8S, 11S), and (6S, 8R, 11R). These adducts were synthesized into 12-mer oligodeoxynucleotides, inserted into a DNA shuttle vector and evaluated for the ability of each stereoisomer to induce mutagenesis when replicated through mammalian cells. The resultant mutagenicity of these adducts was related to their stereochemistry, in that two of the HNE-dG adducts, (6R, 8S, 11R) and (6S, 8R, 11S), were significantly more mutagenic than the (6R, 8S, 11S) and (6S, 8R, 11R) HNE-dG adducts. These data conclusively demonstrate that HNE-derived DNA adducts can be mutagenic in mammalian cells and their ability to cause mutations is dictated by their stereochemistry.

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Section: Discussionmentioning

confidence: 97%

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

Fernandes

Wang

Rizzo

et al. 2003

Environ and Mol Mutagen

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“…The formation of the highly reactive 4-HNE occurs through reactive oxygen species-induced peroxidation of polyunsaturated fatty acids (Yi et al 1997, Comporti 1998. Since the membranes of spermatozoa, transported by the vas deferens, contain higher concentrations of polyunsaturated fatty acids in comparison with other cell types (Aitken 1994), the remarkable strong expression of AKR1B7 within this organ may represent a protective mechanism against this toxic aldehyde, ensuring sperm viability.…”

Section: Introductionmentioning

confidence: 99%

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

Baumann¹,

Davies²,

Peters³

et al. 2007

Reproduction

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AKR1B7 (aldo-keto reductase family 1, member 7; also known as mouse vas deferens protein) is a member of the AKR superfamily, and has been suggested to play a role in detoxifying processes on account of its preferred substrates, 4-hydroxynonenal and isocaproaldehyde. High levels of protein expression were found in the vas deferens and the adrenal gland, where sustained expression is dependent on androgen or ACTH respectively. Recently, a remarkable induction of AKR1B7 expression has been reported in the ovary following exogenous injections of LH. In the present study, we confirm this regulation physiologically during the estrous cycle, observing Akr1b7 expression to be restricted to the theca and stromal cells of the proestrus ovary. To further investigate the role of this detoxifying enzyme in both male and female reproduction, we generated knockout mice deficient in AKR1B7. Although AKR1B7 expression in the vas deferens is considerable and tightly regulated in the ovary of wild-type animals, homozygous mutant animals were found to be viable and no reproductive phenotype was observed. Ovarian follicle maturation and spermatozoa parameters remained normal in the absence of this protein. The determination of serum progesterone revealed an increase in hormone concentration in metestrus, while progesterone was found to be decreased in the estrus phase of the cycle in knockout females.

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“…A cadeia lateral no C-6 do novo anel revela qual enal gerou o aduto. Uma vez que os adutos contêm dois novos centros quirais, os produtos compreendem uma mistura de diastereoisômeros 222,223 . Dentre os trans-2-alcenais, os mais estudados são acroleína [H 2 C=CH-HC=O] e crotonaldeído [H 3 C-CH=CH-HC=O].…”

Section: Danos Basais Em Dna: III Propanoadutosunclassified

Formação de adutos exocíclicos com bases de DNA: implicações em mutagênese e carcinogênese

Loureiro¹,

Mascio²,

Medeiros³

2002

Quím. Nova

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Recebido em 5/7/01; aceito em 28/11/01 EXOCYCLIC DNA ADDUCTS: IMPLICATIONS IN MUTAGENESIS AND CARCINOGENESIS. A number of ring-extended DNA adducts resulting from reaction of a,b-unsaturated aldehydes, or their epoxides, with DNA bases have been characterized in recent years. These adducts can lead to miscoding during DNA replication which, if not repaired, result in mutations that can contribute to cancer development. Recently, the use of ultrasensitive methods allowed the detection of background levels of etheno DNA adducts in tissues of untreated animals and humans suggesting the existence of endogenous sources of reactive intermediates. In this review, we briefly summarize the recent advances in the chemistry of these DNA lesions.Keywords: exocyclic DNA adducts; etheno DNA adducts; lipid peroxidation. INTRODUÇÃOÉ muito antiga a observação de que a exposição dos seres humanos a determinadas substâncias presentes no meio ambiente ou no seu local de trabalho pode levar ao desenvolvimento de câncer. Já no final do século XVIII foi relatado que a ocorrência de câncer de escroto em limpadores de chaminés poderia estar relacionada com a deposição de fuligem e alcatrão nas pregas escrotais. Posteriormente foi mostrado que a aplicação repetida de alcatrão de hulha na pele de animais levava ao eventual desenvolvimento de tumores malignos no sítio da aplicação. Hoje sabemos que o alcatrão de hulha contém hidrocarbonetos aromáticos carcinogênicos, como o benzo[a]pireno. No século XIX foi percebida uma associação entre a exposição de pintores a aminas aromáticas, tal como benzidina, e o desenvolvimento de câncer na bexiga. Somente após 1930 foi demonstrada a associação entre a exposição de animais a diversas aminas aromáti-cas e o desenvolvimento desse tipo de câncer. Atualmente são conhecidas várias substâncias químicas carcinogênicas 1 . Chama-se carcinogênese o processo de conversão de uma célula normal em uma célula maligna, sendo que os agentes indutores desse processo são denominados carcinógenos. Usualmente é necessá-ria a exposição repetida aos carcinógenos para que haja o desenvolvimento de tumores malignos. Esse desenvolvimento ocorre muito lentamente devido à natureza complexa da carcinogênese, a qual pode ser dividida em três estágios: a iniciação, a promoção e a progressão, seqüência de eventos que foi esclarecida no decorrer dos últimos 20 anos 2 . Freqüentemente, após a alteração inicial, aparecem novas populações celulares que representam a evolução de células normais para células pré-neoplásicas, pré-malignas e malignas 3,4 . A iniciação é causada por uma alteração irreversível do DNA, como a reação dessa molécula com substâncias carcinogênicas. Assim, mecanismos de detoxificação de carcinógenos, reparo do DNA e eliminação das células que tenham DNA modificado (por apoptose, por exemplo) são importantes para a proteção contra a iniciação do câncer. Para que a iniciação ocorra, é necessário que haja não só a modificação do DNA, mas também a sua replicação e a proliferação celular, de modo que a mutação in...

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Synthesis and ³²P-Postlabeling/High-Performance Liquid Chromatography Separation of Diastereomeric 1,N²-(1,3-Propano)-2‘-deoxyguanosine 3‘-Phosphate Adducts Formed from 4-Hydroxy-2-nonenal

Cited by 55 publications

References 35 publications

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

Formação de adutos exocíclicos com bases de DNA: implicações em mutagênese e carcinogênese

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Synthesis and 32P-Postlabeling/High-Performance Liquid Chromatography Separation of Diastereomeric 1,N2-(1,3-Propano)-2‘-deoxyguanosine 3‘-Phosphate Adducts Formed from 4-Hydroxy-2-nonenal

Cited by 55 publications

References 35 publications

Site‐specific mutagenicity of stereochemically defined 1,N2‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

Site‐specific mutagenicity of stereochemically defined 1,N2‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

Formação de adutos exocíclicos com bases de DNA: implicações em mutagênese e carcinogênese

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Product

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Synthesis and ³²P-Postlabeling/High-Performance Liquid Chromatography Separation of Diastereomeric 1,N²-(1,3-Propano)-2‘-deoxyguanosine 3‘-Phosphate Adducts Formed from 4-Hydroxy-2-nonenal

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells

Site‐specific mutagenicity of stereochemically defined 1,N²‐deoxyguanosine adducts of trans‐4‐hydroxynonenal in mammalian cells