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Structural limits of specificity of methylcholanthrene-repressible nitrosamine N-dealkylases. inhibition by analog substrates

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Summary

The dealkylation of dsimethyl-, diethyl- and dipropylnitrosamine by hepatic microsomes of Sprague-Dawley rats is repressed by pretreatment of the animals with 3-methylcholanthrene (MC), and this repression progressively decreases with the increase of alkyl chain length. In contrast to its effect on the demethylation of dimethylnitrosamine (DMN), in vivo phenobarbital induces rather than represses the deethylation of diethylnitrosamine. The rates of demethylation of the DMN analog substrates (dimethylformamide, dimethylacetamide, dimethylpropionamide, and dimethylbutyramide), although low as compared to DMN, increase with the acyl chain length. These analogs are potent in vitro inhibitors of DMN demethylation when used in combination with DMN as substrates, and the inhibition decreases with the length of the acyl chain. Dimethylaminoacetone, which corresponds to the insertion of a CH2 group between the N atom and the carbonyl group in dimethylacetamide, is not an in vitro inhibitor of DMN demethylation; the demethylation rates are additive when this compound is used as substrate in combination with DMN. The rate of demethylation of dimethylaminoacetone is substantially higher than the rates of the dimethylacylamides, and is significantly repressed by MC-pretreatment. The rate of demethylation of methylphenylnitrosamine is not influenced by MC-pretreatment; the compound is, however, a potent inhibitor of demethylation when used as substrate in combination with DMN. The demethylation rates of 1,1-dimethylhydrazine (the reduction product of DMN) and dimethylaniline are not influenced by MC-pretreatment; neither do they affect the overall rate of demethylation when used as substrate in combination with DMN.

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Authors and Affiliations

  1. Seamen's Memorial Research Laboratory, US Public Health Service Hospital, 210 State Street, 70118, New Orleans, LA, USA

    J. C. Arcos, G. M. Bryant, K. M. Pastor & M. F. Argus

  2. Department of Medicine, Tulane University Medical Center, New Orleans

    J. C. Arcos, G. M. Bryant, K. M. Pastor & M. F. Argus

Authors
  1. J. C. Arcos
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  2. G. M. Bryant
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  3. K. M. Pastor
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  4. M. F. Argus
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Additional information

This investigation was supported by the USPHS Research Grants CA-13206 and CA-15111 from the National Cancer Institute and Grant No. 922 M from the Council for Tobacco Research. Preliminary communication presented at the FASEB Meeting, Atlantic City, N.J. (Bryant et al., 1975).

Recipient of a Faculty Research Award from the American Cancer Society.

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Arcos, J.C., Bryant, G.M., Pastor, K.M. et al. Structural limits of specificity of methylcholanthrene-repressible nitrosamine N-dealkylases. inhibition by analog substrates. Z. Krebsforsch. 86, 171–183 (1976). https://doi.org/10.1007/BF00284005

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  • DOI: https://doi.org/10.1007/BF00284005

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