Characterization of 7,12-dimethylbenz[a]anthracene-adenine nucleoside adducts

Sc, Cheng; As, Prakash; Ma, Pigott; Bd, Hilton; Jm, Román Piñana; Hm, Lee; Rg, Harvey; Dipple, Anthony

doi:10.1021/tx00004a005

Cited by 46 publications

(33 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human normal liver tissues were obtained from the National Cancer Institute Cooperative Human Tissue Network (Philadelphia, PA). The ages of the donors (nonsmokers and not alcoholics) ranged from 18 to 60 yr. The liver specimens were collected and frozen within 6 h after surgery or death.…”

Section: Isolation Of Liver Microsomesmentioning

confidence: 99%

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

et al. 1996

View full text Add to dashboard Cite

7,12-Dimethylbenz[a]anthracene (DMBA), a potent carcinogen, requires metabolic activation by cytochrome P450s (P450s) to electrophilic metabolites that result in DNA modification, mutagenicity, and carcinogenicity. In this study, we used eight human forms, four rodent forms, and one rabbit form of P450 expressed from recombinant vaccinia or baculovirus vectors to define their specificity for metabolizing DMBA. Of the eight human P450s, 1A1 was the most active (specific activity = 14.7 nmol/min/nmol of P450) in total metabolism of DMBA and showed approximately 6- to 33-fold more activity than other P450s, 2B6, 2C9, and 1A2 were also capable of metabolizing DMBA (2.0-2.5 nmol/min/nmol of P450), whereas 2C8, 2E1, 3A4, and 3A5 exhibited relatively low activities. Among animal P450s, mouse 1A1 exhibited activity similar to that of human 1A1 and had 5.0- to 37-fold more activity than other rodent and rabbit P450s. In regard to enzyme regioselectivity, most human and rodent P450s predominantly formed the 8,9-diol, but human 2B6 and rat 2B1 preferentially formed the 5,6-diol. In the production of monohydroxymethyl metabolites, all the enzymes yielded more 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOM12MBA) than 12-hydroxymethyl-7-methylbenz[a]anthracene (7M12HOMBA), except for human 1A1, which presented the reverse selectivity. Human liver microsomes from 10 organ donors were shown to metabolize DMBA and in most circumstances generated the metabolic profile DMBA trans-8,9-dihydrodiol > 7HOM12MBA > or = DMBA trans-5,6-dihydrodiol > or = 7,12-dihydroxymethylbenz[a]anthracene > 7M12HOMBA > DMBA trans-3,4-dihydrodiol. Thus, the combined activity of hepatic microsomal 2C9, 1A2, and 2B6 may contribute to the metabolic activation and the metabolism of DMBA in normal human liver.

show abstract

Section: Isolation Of Liver Microsomesmentioning

confidence: 99%

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

et al. 1996

View full text Add to dashboard Cite

show abstract

“…DMBA-3,4-dihydrodiol is a more potent tumor initiator than DMBA (33), and several stable DMBA diol epoxide-DNA adducts have been identified (34,35). DMBA-3,4-dihydrodiol is carcinogenic through its diol epoxide, but the activity of the parent DMBA is initiated by its radical cation, based on the relative formation of depurinating vs. stable adducts and the results of the tumorigenicity experiments descnibed above.…”

mentioning

confidence: 99%

Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

Chakravarti

Pelling

Cavalieri

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

187

208

View full text Add to dashboard Cite

Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G -* T and A --T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo-[a,l pyrene (DB[a,l]P), DB [a,l]P-11,12-dihydrodiol, anti-DB[a,l]P-11,12-diol-13,14-epoxide, DB[a,l]P-8,9-dihydrodiol, 7,12-dimethylbenz [a] anthracene (DMBA), and 1,2,3,4-tetrahydro-DMBA consistently induced a CAA -> CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC -* GTC mutation in codon 13 in 54% of tumors and a CAA -> CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sites generated by loss of hydrocarbon-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.The ras family of oncogenes includes the closely related H-, Kirsten-, and N-ras genes.

show abstract

“…DMBA is metabolized by CYP1A1 and CYP1B1, which convert DMBA to the ultimate carcinogen 1, 2-epoxide-3, 4-diol DMBA (Anqus et al, 1999;Buters et al, 1999;Kawajiri and Ikuta, 1999;Sharma et al, 2012), which form adducts with DNA and it leads to carcinogenesis (Cheng et al, 1988). Suppression of CYP1A1 enzyme activity by TEO can reduce the effect of DMBA induced carcinogenesis.…”

Section: Inhibition Of Cytochrome P450 Enzymes In Vitromentioning

confidence: 99%

Chemopreventive Activity of Turmeric Essential Oil and Possible Mechanisms of Action

Liju¹,

Jeena²,

Kuttan³

2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Asian Pac J Cancer Prev, 15 (16), 6575-6580 IntroductionMany human cancers are caused by chemical carcinogens, such as polycyclic aromatic hydrocarbons, heterocyclic amines, aromatic amines etc present in our environment. Continued exposure of these substances to human cells leads to genomic instability, including repair deficiency and accumulation of genetic alteration (Ames, 1983). Mutation is a major factor in carcinogenesis and incidence of cancer may be reduced by decreasing the rate of mutations induced by various chemical mutagens. Many carcinogens are activated through Phase I (cytochrome p450) enzymes present in endoplasmic reticulum of the liver cells. Induction of Phase II detoxification enzymes, such as glutathione S-transferase and UDP-glucuronyl transferase, is another mechanisms of protection against carcinogenesis (Piengchai et al., 2011). Modulating these enzymes may reduce cancer incidence.Spices which are widely used as food ingredient exhibits different pharmacological properties. Essential oils from spices are volatile compounds produced as secondary metabolites. The essential oil from Curcuma longa rhizome is a complex mixture obtained by steam distillation. A total number of 12 components of the essential oil are identified by GC-MS analysis and the principal compounds include ar-turmerone (61%), Department of Biochemistry, Amala Cancer Research Centre, Kerala, India *For correspondence: amalacancerresearch@gmail. com, amalaresearch@hotmail.com AbstractThis study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12 -dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide (NaN 3 ), 4-nitro-O-phenylenediamine (NPD) and N-methyl-N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mecha...

show abstract

Characterization of 7,12-dimethylbenz[a]anthracene-adenine nucleoside adducts

Cited by 46 publications

References 16 publications

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

Chemopreventive Activity of Turmeric Essential Oil and Possible Mechanisms of Action

Contact Info

Product

Resources

About