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Molecular Dosimetry of Polycyclic Aromatic Hydrocarbon Epoxides and Diol Epoxides via Hemoglobin Adducts¹

Department of Chemistry, Division of Toxicology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Ten reactive metabolites of five polycyclic aromatic hydrocarbons and styrene were investigated to determine the generality of ester adduct formation with human hemoglobin in the form of RBC and hydrolysis to the corresponding tetrahydrotetrols or dihydrodiols. No exceptions were noted among the compounds tested, which included the anti-diol epoxides of benzo[a]pyrene (BaP), chrysene, and benz[a]anthracene; the syn-diol epoxide of BaP; a mixture of syn- and anti-diol epoxides of benzo[e]pyrene; and epoxides of styrene, benzo[e]pyrene, BaP, and cyclopenta[c,d]pyrene. A test of the propensity of the simplest benzylic epoxide, styrene oxide, to form esters that hydrolyze via a B_AL1 mechanism was performed. Hydrolysis of styrene oxide-adducted hemoglobin in H₂¹⁸O at neutral pH yielded ¹⁸O incorporation results that suggest this mechanism of hydrolysis is operant to a minor degree in styrene oxide-hemoglobin ester adducts. A method was developed for the isolation and quantification of the polycyclic aromatic alcohols, which consists of enzymatic proteolysis, immunoaffinity chromatography, and gas chromatography-mass spectrometry or fluorimetry. The method allows for routine analysis of hemoglobin from individual samples as small as 1 ml of whole blood. Analysis of blood from different human populations revealed that hemoglobin adducts of the anti-diol epoxide of BaP dominated the spectrum of adducts formed by the selected metabolites.

¹ This investigation was supported by DHHS Shared Instrument Program Grant 1-S10-RR1901 and NIH Grants ES01640, ES02109, ES04675, and CA44306.

² Supported by postdoctoral fellowships from NIH Grant ES17020 and American Cancer Society Grant SIG-11-I.

³ Present address: MRC Toxicology Unit, Carshalton, Surrey SM5 4EF, England.

⁴ Present address: Glaxo Inc., Research Triangle Park, NC 27709.

⁵ To whom requests for reprints should be addressed, at Room 56-309, Massachusetts Institute of Technology, Department of Chemistry, Division of Toxicology, Cambridge, MA 02139.

Received 1/12/90. Revised 4/10/90.

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