A 7-Hydroxymethyl Sulfate Ester as an Active Metabolite of 7,12-Dimethylbenz[
            <i>a</i>
            ]anthracene

Watabe, Tadashi; Ishizuka, Tsuneo; Isobe, Masakazu; Ozawa, Naok̆i

doi:10.1126/science.6800033

Cited by 191 publications

(60 citation statements)

References 16 publications

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“…To our knowledge, benzylic alcohols are the only group for which a positive result has been obtained in a short-term test using an exogenous sulfate-conjugating system for the activation (5)(6)(7). In the present study, it was demonstrated that this effect involves a special mechanism, namely, substitution of the polar sulfate group by a nonpolar halogen group.…”

Section: Toxicological Implications Of Hampered Transport Of Active Smentioning

confidence: 70%

“…Strikingly, however, the addition of a sulfate-conjugating system usually decreased the mutagenicity of aromatic amines and their metabolites in Salmwnella typhimurium, whereas the covalent binding to isolated nucleic acids was enhanced (2)(3)(4). On the other hand, Watabe et al (5)(6)(7) have observed DNA binding as well as bacterial mutagenicity for benzylic sulfate esters and alcohols, the latter requiring the presence of a sulfotransferase-containing metabolic system. To study structural and metabolic parameters governing this mutagenicity, we have synthesized a series of benzylic alcohols and sulfate esters.…”

Section: Introductionmentioning

confidence: 98%

“…The product was purified by flash chromatography and finally recrystallized from n-hexane. HMPS was synthesized by sulfatation of HMP as described by Watabe et al (5). Heating of HMP in the presence of thionyl chloride produced 1-chloromethylpyrene (CIMP).…”

Section: Methodsmentioning

confidence: 99%

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Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells.

Glatt

Henschler

Phillips

et al. 1990

Environ Health Perspect

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Methylated polycyclic aromatic hydrocarbons are common in the human environment. Many of them are stronger carcinogens than their purely aromatic congeners. They may be metabolized to benzylic alcohols. We report here on biochemical and toxicological characteristics of 1-hydroxymethylpyrene (HMP), a typical representative of this class of compounds. Rat liver cytosol, fortified with 3'-phosphoadenosine-5'-phosphosulfate, converted HMP into its sulfate ester (HMPS). HMPS bound covalently to isolated DNA. In physiological buffer at 370C, HMPS had a half-life of 2 min, the major decomposition product being HMP. Thus, cyclic activation is possible. When Cl-anions were present at physiological concentrations, an additional reaction product of HMPS, 1-chloromethylpyrene (CIMP), could be identified on the basis of its chromatographic properties and its mass spectrum, using the authentic standard for comparison. CIMP was shorter-lived in buffer than HMPS. CIMP reacted with DNA, the adduct pattern in the 32P-postlabeling analysis being similar, or identical, to that of HMPS. CIMP proved to be a very potent mutagen in Salmonella typhimurium, whereas HMPS, and HMP in the presence of a sulfateconjugating system, showed strong mutagenicity only when Cl-or Br-ions were present in the exposure buffer. It is concluded that HMPS is capable of reacting with DNA, but is hampered in its distribution by membrane barriers. Strikingly, a CIMP intermediate is produced, which can act as a transport form to overcome membrane barriers. Among 10 investigated tissues, HMP-activating sulfotransferases were found at appreciable levels only in the liver, and there the activity in parenchymal cells exceeded that in Kupffer cells by a factor of -200. Distribution processes and their restrictions may, therefore, be important factors determining the toxicology of benzylic alcohols and other compounds activated through conjugation with sulfate.

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Section: Toxicological Implications Of Hampered Transport Of Active Smentioning

confidence: 70%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells.

Glatt

Henschler

Phillips

et al. 1990

Environ Health Perspect

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“…Sulfonation is generally thought to be a detoxication process; however, the enzyme also activates certain promutagens, e.g. 5-methylchrysene (Blanchard et al, 2004), DMBA, cyclopenta [c,d,]pyrene and benzo [a]pyrene (Watabe et al, 1982;Surh et al, 1987Surh et al, , 1993Surh & Tannenbaum, 1995) by a mechanism that involves the conjugation of benzylic alcohols. Six cytosolic SULTs are known to be expressed in humans, including phenol SULTs, hydroxy SULTs and estrogen SULTs (Raftogianis et al, 1997;Daly, 2003;Moreno et al, 2005).…”

Section: (X) Epoxide Hydrolasementioning

confidence: 99%

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

Hellou¹,

Beach²,

Leonard³

et al. 2012

Polycyclic Aromatic Compounds

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initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, life-style factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in chemical carcinogenesis Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications -whether for sale or for noncommercial distribution -should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: permissions@who.int).The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data NOTE TO THE READERThe term 'carcinogenic risk' in the IARC Monographs series is taken to mean that an agent is capable of causing cancer under some circumstances. The Monographs evaluate cancer hazards, despite the historical presence of the word 'risks' in the title.Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that it is not carcinogenic.The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No recommendation is given for regulation or legislation.Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information available to the Section of IARC Monographs, International Agency for...

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“…SULT1A1 catalyze the sulfonation of N-hydroxy derivatives of arylamines and heterocyclic amines, which are presented in tobacco smoke, to form more reactive DNA-damaging electrophiles (Ozawa et al, 1994;Chou et al, 1995). Sulfonation can also activate another major class of tobacco carcinogens, polycyclic aromatic hydrocarbons (PAHs) and nitro PAHs (Watabe et al, 1982;Surh et Ozawa et al, 1998;Hirata et al, 2008). Among these, a common polymorphism (G638A) at codon 213 in exon 7 of SULT1A1 gene causes an Arg to His amino acid substitution.…”

Section: Introductionmentioning

confidence: 99%

SULT1A1 Arg213His Polymorphism and Lung Cancer Risk: a Meta-analysis

Liao

Liu²,

Wang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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A 7-Hydroxymethyl Sulfate Ester as an Active Metabolite of 7,12-Dimethylbenz[ a ]anthracene

Cited by 191 publications

References 16 publications

Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells.

Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells.

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

SULT1A1 Arg213His Polymorphism and Lung Cancer Risk: a Meta-analysis

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