A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism

Abstract

Isothiocyanates are small molecules characterized by high chemical reactivity that allows them to interact readily with cellular constituents eliciting a plethora of biological activities. They are present exclusively in cruciferous vegetables, as glucosinolates, the intake of which has been associated with cancer chemoprevention. When the physical structure of these vegetables is disturbed, e.g. during mastication, the enzyme myrosinase is released and converts the glucosinolates to isothiocyanates (R-N=C=S), where R can be aliphatic or aromatic. Although sulforaphane, an aliphatic isothiocyanate, has received most attention worldwide, the most extensively studied aromatic isothiocyanate is phenethyl isothiocyanate (PEITC), and there are substantial differences in biological activity between the two sub-classes. In animal cancer models, PEITC effectively antagonized the carcinogenicity of chemicals, especially nitrosocompounds. A principal mechanism of their action is to protect the integrity of DNA by decreasing the levels of the genotoxic metabolites of chemical carcinogens. Extensive studies established that PEITC modulates the metabolism of the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by inhibiting its cytochrome P450-mediated bioactivation. Moreover, PEITC is a potent inducer of detoxification enzymes such as quinone reductase, glutathione S-transferase and glucuronosyl transferase. PEITC is rapidly absorbed and is characterized by a large bioavailability; Cmax concentrations achieved in plasma after dietary intake are sufficient to modulate carcinogen metabolism. PEITC is primarily metabolized by glutathione conjugation and is excreted in the urine and bile as the mercapturate. The ability of PEITC to perturb carcinogen metabolism through modulation of cytochrome P450 and phase II detoxification enzymes is comprehensively and critically reviewed.

In vitro Evaluation of Brassica sprouts for its Antioxidant and Antiproliferative Potential

“…There was also a report on comparison of bioactive phytochemical content and release of ITCs in selected Brassica sprouts [20] . Their overall protective effect has been generally attributed to the modulation of xenobiotic metabolilizing enzymes and enzymatic antioxidative defense system [21] . However, whether these effects can mainly be ascribed to a single class of molecules, e.g.…”

Indole phytoalexin derivatives induce mitochondrial-mediated apoptosis in human colorectal carcinoma cells

“…They act through multiple mechanisms in the prevention of cancer. These include inhibition of metabolic activation or induction of metabolic deactivation of procarcinogens[10,11], inhibition of key steps in angiogenesis[12], induction of apoptosis and cell cycle arrest[13], inhibition of metastasis[14] or suppression of different signaling pathways associated with cell proliferation and growth[15,16]. …”

Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines

“…[7] Although electrophilic, radical, and nucleophilic trifluoromethylation approaches are effective, [8] CF 3 -substituted free amines cannot be easily obtained by using these approaches because the nitrogen atom in NCF 3 must, usually,b ea ttached to another heteroatom (nitrogen, oxygen, or sulfur) [8c-f] or because the trifluoromethylation reagent is unstable and highly reactive. [9] This convenient protocol has awide range of potential applications for the synthesis of isothiocyanates. Va rious NÀaryl-NÀalkyl amines were converted to the desired products in high yields irrespective of whether the aryl groups contained electron-rich, -neutral, or -deficient substituents (A1-A21).…”