4299

Our previous studies have shown that the natural β-glucuronidase (βG) inhibitor D-glucaro-1,4-lactone (1,4-GL) and its precursors such as D-glucarates detoxify chemical carcinogens that undergo glucuronidation and inhibit chemically induced experimental tumorigenesis, in part, by inhibiting the enzyme β-glucuronidase. Carcinogen-mediated labilization of lysosomal enzymes such as βG is often associated with the general process of inflammation. Therefore, the primary goal of this study was to demonstrate that exposing the skin of SENCAR mice to the natural βG inhibitor, i.e., 1,4-GL and its precursor D-glucuronic acid lactone (GUL), prior to and during 7,12-dimethylbenz[a]anthracene (DMBA) treatment inhibits selected biomarkers of inflammation in the DMBA-induced mouse skin complete carcinogenesis model, i.e., the 4-week inflammatory-hyperplasia assay. Another goal of the present study was to show that dietary 1,4-GL and GUL also inhibit DMBA-induced hyperplasia and inflammation in SENCAR mice. Topical administration of 1,4-GL or GUL prior to repetitive, high-dose DMBA treatment markedly and in a dose-related manner inhibited DMBA-induced epidermal hyperplasia (i.e., up to 57%). DMBA-mediated Ha-ras mutations in codon 61 were reduced by up to 78%. DMBA-induced inflammation as measured by dermal leukocyte counts and immunologically was inhibited by up to 37% by topical 1,4-GL but not by GUL. The inhibition of cellular proliferation and inflammation coincided with the inhibition of βG expression. Dietary 1,4-GL and GUL also inhibited in a dose-dependent fashion DMBA-induced hyperplasia and inflammation in SENCAR mice. Thus, the present study suggests that in the DMBA-induced complete skin carcinogenesis model, 1,4-GL and its precursor GUL have antiproliferative properties as well as anti-inflammatory properties. However, the number of inflammatory cells in the dermal portion of the skin of SENCAR mice was significantly reduced only by dietary GUL while both topical and dietary 1,4-GL treatments were very effective.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]