Specific targets of alkylating agents in nuclear proteins of cultured hepatocytes

L. C. Boffa, C. Bolognesi, M. R. Mariani

Research output: Contribution to journalArticle

Abstract

We have established a specific correlation between the carcinogenic potency of a series of alkylating agents, with a mechanism of reaction ranging between Ingold's SN1-SN2 (ENU MNU = MNNG EMS DMS = MMS) (Vogel et al., 1979; Bartsch et al., 1983) and specific target sites in the amino acids of nuclear proteins of cultured hepatocytes. More potent carcinogens, that react predominantly with an Ingold's SN1 mechanism, mainly alkylate the amino group of lysine and the guanido group of arginine. Weaker carcinogens, reacting with a mechanism closely resembling an Ingold's SN2, mainly alkylate the sulfhydryl group of the cysteine and the 3 position of the imidazolic ring of histidine. A compound with an intermediate type of reactivity alkylates, to a comparable extent, all 4 of the above-described positions. Although stable DNA damage brought about by alkylating carcinogens is considered to be the most likely cause of neoplastic transformation, epigenetic modifications may also play an important role in the process, especially because of their extreme stability. We have verified the existence of a linear correlation between the Swain-Scott substrate constant (S) of each compound and the amount of alkylation produced at the specific target sites. This type of correlation could be the basis of a 'short-term' genotoxicity assay in a battery of complementary tests.

Original languageEnglish
Pages (from-to)119-123
Number of pages5
JournalMutation Research Letters
Volume190
Issue number2
DOIs
Publication statusPublished - 1987

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Keywords

  • Alkylating agents
  • cultured
  • DNA damage
  • Hepatocytes
  • nuclear
  • Proteins
  • Swain-Scott substrate constant

ASJC Scopus subject areas

  • Genetics
  • Toxicology
  • Medicine(all)

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