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Alteration in the capacities of carcinogen metabolizing system of mouse-livers during pretreatment with various

M Mostafa1, K Chalvardjian, H Lami

  • 1ARABIAN GULF UNIV,COLL APPL SCI,MANAMA,BAHRAIN.

Oncology Reports
|May 25, 2011
PubMed

Insights

Antineoplastic drugs alter carcinogen metabolism in mice. Alkylating agents and repeated antimetabolites increase enzyme activity, while actinomycin-D inhibits it, impacting toxicity and carcinogenicity.

Area of Science:

  • Pharmacology and Toxicology
  • Drug Metabolism
  • Carcinogenesis Research

Background:

  • Antineoplastic drugs are crucial for cancer treatment but can have complex interactions with the body's metabolic systems.
  • Understanding how these drugs affect carcinogen metabolism is vital for managing treatment-related toxicities and long-term health risks.

Purpose of the Study:

  • To investigate the impact of single and repeated doses of various antineoplastic drugs on the carcinogen-metabolizing enzyme activity in mice liver microsomes.
  • To determine the specific effects of different drug classes, including alkylating agents, antibiotics, and antimetabolites, on key metabolic enzymes like cytochrome P450.

Main Methods:

  • Mice were treated with single or repeated doses of antineoplastic drugs (chlorambucil, melphalan, busulfan, actinomycin-D, 5-fluorouracil, methotrexate).
  • Liver microsomes were analyzed for the activity of carcinogen-metabolizing enzymes, including N-nitrosodimethylamine demethylases and aryl hydrocarbon hydroxylase.
  • Hepatic content of cytochrome P450 was also quantified.

Main Results:

  • Alkylating agents (chlorambucil, melphalan, busulfan) significantly increased carcinogen-metabolizing enzyme activity.
  • Antimetabolites (5-fluorouracil, methotrexate) decreased activity with single doses but increased it with repeated doses.
  • Actinomycin-D consistently inhibited enzyme activity, while cytochrome P450 levels increased with most drugs upon repeated administration (except busulfan).

Conclusions:

  • Different classes of antineoplastic drugs differentially modulate carcinogen metabolism, with significant implications for drug-induced toxicity.
  • Repeated dosing regimens can alter metabolic enzyme activity, potentially influencing the risk of secondary carcinogenicity.
  • These findings highlight the need for careful consideration of drug metabolism when evaluating the safety and efficacy of antineoplastic therapies.

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