title: Modulation of biomarkers related to tumor initiation and promotion in mouse skin by a natural β-glucuronidase inhibitor and its precursors.
abstract: Carcinogen-mediated labilization of lysosomal enzymes such as β-glucuronidase (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 D-glucaro-1,4-lactone (1,4-GL) and its precursor D-glucuronic acid-γ-lactone (GUL), prior to and during 7,12-dimethylbenz[α]anthracene (DMBA) treatment inhibits not only epidermal hyperplasia but also inflammation in the mouse skin complete carcinogenesis model, i.e., the 4-week inflammatory-hyperplasia assay. 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% by 1,4-GL. 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. Thus, the present study suggests that in the DMBA-induced complete skin carcinogenesis model, 1,4-GL when applied topically had both anti-proliferative properties as well as anti-inflammatory properties, whereas GUL had only anti-proliferative when applied topically. However, the number of inflammatory cells in the dermal portion of the skin of mice was significantly reduced by dietary treatment of GUL, whereas both topical and dietary treatments with 1,4-GL were very effective.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. magdagorka@hotmail.com
authors.forename: Magdalena C
authors.initials: MC
authors.lastname: Kowalczyk
authors.forename: Erick
authors.initials: E
authors.lastname: Spears
authors.forename: Maciej
authors.initials: M
authors.lastname: Narog
authors.forename: Robert
authors.initials: R
authors.lastname: Zoltaszek
authors.forename: Piotr
authors.initials: P
authors.lastname: Kowalczyk
authors.forename: Margaret
authors.initials: M
authors.lastname: Hanausek
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Walaszek
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002273:Carcinogens; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003877:Dermatitis, Contact / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005937:Glucaric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005965:Glucuronates / Q000008:administration & dosage / Q000494:pharmacology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006965:Hyperplasia / Q000139:chemically induced; D018836:Inflammation Mediators / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D007958:Leukocyte Count; D051379:Mice; D018632:Mice, Inbred SENCAR; D009369:Neoplasms / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D016588:Anticarcinogenic Agents; D015415:Biomarkers; D002273:Carcinogens; D005965:Glucuronates; D018841:HSP90 Heat-Shock Proteins; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; C004940:glucuronolactone; D015127:9,10-Dimethyl-1,2-benzanthracene; C009194:saccharolactone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005966:Glucuronidase; D003849:Deoxyguanosine; D005937:Glucaric Acid