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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh098
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received September 8, 2003; accepted January 27, 2004
© 2004 Society of Toxicology

Carcinogenicity

Modulation of Carcinogen Metabolism and DNA Interaction by Calcium Glucarate in Mouse Skin

Krishna P. Gupta 1* and Jaya Singh 1

1 Environmental Carcinogenesis Division, Industrial Toxicology Research Center, Post Box No. 80, Mahatma Gandhi Marg, Lucknow - 226001 (India)

* To whom correspondence should be addressed. E-mail: krishnag522{at}yahoo.co.in.


  Abstract

Almost all the polycyclic aromatic hydrocarbons require metabolic activation to extert their carcinogenic activity. Environmental carcinogen BP is carcinogenic only after its metabolic transformation to a reactive intermediate, which can then bind to cellular macromolecules. Inhibition of DMBA-DNA binding generally accompanied inhibition of tumor initiation as most inhibitors of initiation interfere with the metabolic activation of the initiator. The importance of Carcinogen-DNA interaction and the enzymes involved in the metabolism of carcinogenic polycyclic hydrocarbons (PAH) has led to a search for inhibitors which would be useful in modifying the cancer causing effects of the PAHs. Effect of Calcium Glucarate (Cag), a naturally occurring nontoxic compound, on carcinogen metabolism and DNA interaction was studied. Cag inhibited [3H] Benzo[a]pyrene (BP) binding to both calf thymus DNA in-vitro and to epidermal DNA in-vivo. Application of Cag to skin caused a dose dependent inhibition of [3H] BP binding to epidermal DNA. Since the relevance of the in vivo results to the in-vitro situation must be firmly established, we followed the in vitro effect of Cag on [3H] BP binding to calf thymus DNA and observed that Cag inhibited the [3H] BP binding to calf thymus DNA in presence of microsomes prepared from animals treated with DMBA. Related events like DNA synthesis or carcinogen metabolism were also studied. For assessing the DNA synthesis, thymidine kinase was used as marker. Cag caused a dose dependent inhibition of DMBA induced thymidine kinase activity. At the same time Cag caused a marked inhibition of DMBA induced aryl hydrocarbon hydroxylase (AHH) activity, an enzyme responsible for the metabolism of polycyclic aromatic hydrocarbons like BP, under both conditions in-vivo as well as in-vitro. The study indicates that Cag exert its antitumor effect possibly by inhibiting the Carcinogen - DNA binding which appears to be due to reduced DNA synthesis and AHH activity.

Key Words: Calcium Glucarate, skin, Carcinogen metabolism, DNA binding, Thymidine kinase .


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