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Conservation of Histone Carcinogen Adducts during Replication: Implications for Long-Term Molecular Dosimetry¹

Department of Chemistry, Division of Toxicology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [C. C. Ö., I. V., P. L. S., S. R. T.]

The effect of cell replication on histone-carcinogen adducts was investigated by determining the specific adduct levels as a function of time following carcinogen treatment of human TK6 cells grown in culture. Core histones isolated from cells treated with aflatoxin B₁ or r-7,t-8 dihydroxy-t-9,t-10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene exhibited a decrease over five generations in specific adduct level that did not exceed the decrease expected as a result of dilution with newly synthesized protein except during the early phase (<1 generation) of the experiment when loss of chemically unstable adducts might occur. Similar kinetics without the initial, more rapid phase was observed when cells were treated with N-nitroso-N-methylurea. Multigeneration stability of aflatoxin B₁ and N-nitroso-N-methylurea adducts that formed on histone H1 was also observed; in these experiments it was not possible to determine if there was an initial phase in the kinetics. These experiments indicate that cell replication does not result in the repair or removal of adducted histones, establishing the feasibility of using histone-carcinogen adducts for molecular dosimetry purposes.

¹ This work was supported by National Institute of Environmental Health Services Grants ES04675 and ES02109.

² Supported by National Institute of Environmental Health Services Grant ES07020.

³ Supported by Knoll AG, Ludwigshafen, Germany.

⁴ Present address: Repligen Corp., 1 Kendall Square, Cambridge, MA 02139.

⁵ To whom requests for reprints should be addressed, at Department of Chemistry, Division of Toxicology, Massachusetts Institute of Technology, Room 56-311, Cambridge, MA 02139-4307.

Received 6/ 6/94. Accepted 8/29/94.

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