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.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…In another study, D-SAL was more therapeutically efficient compared to its natural precursor (D-GL), for reducing epidermal hyperplasia (lethargic tumour promoter) and inflammation in 7,12dimethylbenz(a)anthracene (DMBA)-induced complete skin carcinogenesis of SENCAR mice [125]. Pre and cotreatment of murine models with D-SAL for 4-weeks (twice weekly) by topical administration (0.5e4 mg) or dietary treatment (0.5 and 1%), both significantly reduced epidermal hyperplasia and inflammation by up to 57% of DMBA-controls in a dose-dependent manner.…”

Chemically induced skin carcinogenesis: Updates in experimental models (Review)

“…As demonstrated in another study, the topical administration of the βG inhibitor, D-glucaro-1,4-lactone (1,4-GL), or D-glucuronic acid-γ-lactone (GUL) its precursor, to SENCAR mice with skin carcinogenesis, epidermal hyperplasia was significantly reduced along with a decrease in inflammation ( 107 ). Moreover, Ha-ras mutations were reduced upon experimental therapy.…”

“…Moreover, Ha-ras mutations were reduced upon experimental therapy. That study demonstrated that whether administered topically or through diet, therapy with GUL or 1,4-GL was effective in hindering experimental skin tumorigenesis ( 107 ).…”

Hautschutzmoleküle - Quo vadis? Von der Chemoprävention bis zur kulturell geprägten Dermatoästhetik

“…Lysosomale Enzyme wie ß-Glucuronidase (ßG) sind häufig an hyperplastischen epidermalen Prozessen, an der Karzinogenese und Entzündung beteiligt. Es konnte kürzlich gezeigt werden, dass in dem 7,12-dimethylbenz(a)anthrazen induzierbaren Hautkrebsmodell der natürliche Inhibitor G-Glucuro-1,4-Lacton (1,4GL) sowie sein Vorläufermolekül D-Glucuronsäure-gamma-Lacton (GUL) in einer topischen und diätetischen Applikation erhebliche anti-entzündliche und anti-tumoröse Aktivitäten haben [3]. Viele Pflanzeninhaltsstoffe werden an dem Mehrschrittmodell der Haut zur Karzinogenese geprüft.…”

“…B. die Behandlung von Melasma kaum wissenschaftlich klar strukturiert und standardisiert ist und klinische Studien dringend benötigt werden, um die Wirksamkeit derzeitig marginal effektiver Therapien entscheidend zu verbessern [26]. Störungen in der Melanogenese als klinische Erscheinungsformen von Hautpigmentstörungen sind eng verknüpft mit den Stoffwechselprozessen zur Eumelanin-(dunkel, fotoprotektiv) und zur Phämelanoninbildung (hell, Fotosynthese von Vitamin D [3]); evolutionsbiologisch spielen Glutathion und Melanokortin eine tragende Rolle hinsichtlich der Stimulierung bzw. Inhibition von dunklem und rötlich-hellem Melanin [27].…”