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.