Pharmacokinetics and Pharmacodynamics of Phenethyl Isothiocyanate: Implications in Breast Cancer Prevention

Abstract

Phenethyl isothiocyanate (PEITC)-a naturally occurring isothiocyanate in cruciferous vegetables-has been extensively studied as a chemopreventive agent in several preclinical species and in humans. Pharmacokinetic features of unchanged PEITC are (I) linear and first-order absorption, (II) high protein binding and capacity-limited tissue distribution, and (III) reversible metabolism and capacity-limited hepatic elimination. Membrane transport of PEITC is mediated by BCRP, multidrug resistance-associated protein (MRP) 1, and MRP2 transporters belonging to the ATP-binding-cassette (ABC) family. PEITC is metabolized by glutathione S-transferase (GST) in the liver, with the glutathione conjugate of PEITC undergoing further conversion to mercapturic acid by N-acetyl transferase in rats and humans. PEITC modulates the activity and expression of numerous phase I and phase II drug-metabolizing enzymes and can inhibit the metabolism of procarcinogens to form carcinogens and increase carcinogen elimination. In recent years, several in vitro and in vivo studies have elucidated molecular mechanisms underlying the pharmacodynamics of PEITC in breast cancer that include cancer cell apoptosis by upregulation of apoptotic genes, cell cycle arrest at G2/M phase by generation of reactive oxygen species and depletion of intracellular glutathione, downregulation of the estrogen receptor, decrease in sensitivity to estrogen, and inhibition of tumor metastasis. Inhibition of angiogenesis is one of the recently reported mechanisms of breast cancer prevention by PEITC. Complex pharmacokinetics and pharmacodynamics of PEITC necessitate a systems-biology approach in parallel with PK/PD modeling to develop PEITC as a therapeutic agent for treating cancers.

AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner

“…In no case did we observe that AM841 exhibited the classical CNS actions of a CB 1 receptor agonist and this we attribute to its demonstrated inability to access the brain in significant quantities. One possible explanation for this observation is that the compound is a substrate for one or both of the multidrug resistance proteins (MRP1 and MRP2) as has been reported for the naturally occurring phenethyl isothiocyanate (Ji and Morris, ; Morris and Dave, ). Similar mechanisms have also recently been proposed for the exclusion of other peripherally restricted CB ligands (Pryce et al ., ).…”

Phenethyl Isothiocyanate-Containing Carbomer Gel for Use against Squamous Cell Carcinoma

“…The final concentrations were then made in the phosphate buffer, and solubilized BDT in methanol was added to determine the PEITC concentrations. PETIC should be stored at 2–8 °C [ 23 ]; thus, we kept the formulation at these temperatures during storage. The stability of the formulation under these storage conditions was determined after 30 and 55 days.…”

Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers

“…This is the crucial step that produces highly reactive methylating and pyridyloxobutylating species that react with DNA to form a variety of mutagenic DNA adducts which are critical in lung carcinogenesis by NNK (Figure S1 (8,18). These studies, which have been carried out under a wide variety of conditions both in vitro and in vivo, with protocols varying from acute to chronic, and in some cases mimicking or coinciding with conditions used in the carcinogenicity studies, consistently demonstrate that PEITC decreases the formation of critical reactive metabolites of NNK, resulting in lower levels of DNA adducts in the lung, lower levels of hemoglobin adducts, and decreases in other endpoints, all reflecting inhibition of NNK metabolic activation (7,10–12,15,19–25). Nearly all of this can be traced to the inhibitory effects of PEITC on cytochrome P450 enzymes including human P450s 2A13, 2A6, 1A2, and 2B6, which are catalysts of NNK bioactivation (20,23,24,26–33).…”