1-Hydroxymethylpyrene (HMP), a primary benzylic alcohol, and 4H-cyclopenta[def]chrysen-4-ol (OH-CPC), a secondary benzylic alcohol, were investigated for mutagenicity in Salmonella typhimurium (reversion of the his- strain TA98) in the presence of various xenobiotic-metabolizing systems. In the direct test, HMP was inactive and OH-CPC was very weakly active. In the presence of NADPH-fortified postmitochondrial fraction from rat liver (S9/NADPH), no activation of OH-CPC was observed, whereas strong mutagenic effects were elicited by HMP. In the presence of cytosol and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), both alcohols were activated to potent mutagens. For equal mutagenic effects, approximately 650-fold lower concentrations of HMP were required in the cytosol/PAPS-mediated assay than in the S9/NADPH-mediated assay. The cytosol/PAPS-mediated mutagenicity of both alcohols was 3- to 4-fold enhanced, when KCl (125 mM) was present during the exposure. The authentic chloromethylarenes, 1-chloromethylpyrene and 4-chloro-4H-cyclopenta[def]chrysene, showed very strong direct mutagenicity. These results, taken together with previous findings, indicate that both primary and secondary benzylic alcohols derived from polycyclic aromatic hydrocarbons may be activated by sulfotransferases to electrophilic sulfuric acid esters, and by subsequent substitution reaction to further active species such as benzylic chlorides.
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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