The role of haem oxygenase-1 modulation by isothiocyanates in drug-induced renal failure

• Main Author: Tayem, Yasin I. Y
• Format: Dissertation
• Language: English
• Published: UCL (University College London) 2006

The effect of two isothiocyanates (ITCs), S-(N-benzylthiocarbamoyl)-L-cysteine (BTCC) and S-(N-3-phenylpropylthiocarbamoyl)-L-cysteine (PTCC), in modulating the haem oxygenase-1 (HO-1) pathway was investigated in order to identify a possible strategy for protecting renal cells and tissue against drug-induced toxicity. HO-1 is a versatile inducible enzyme that provides cytoprotection by generating the signalling molecule carbon monoxide (CO) and the antioxidant couple biliverdin (BV) and bilirubin (BR). When cultured renal tubular epithelial (LLC-PK1) cells were exposed to BTCC and PTCC, an increase in HO-1 expression and activity was observed in a time- and concentration-dependent manner. This effect required activation of MAPKs, PKC and PI-3K signal transduction pathways. Interestingly, both BTCC and PTCC caused apoptosis in LLC-PK1 cells when used at concentrations above 20 uM but rendered these cells resistant to apoptotic cell death when low concentrations (5 and 10 uM) were used. In fact, pre-incubation of LLC-PK1 cells with 5 or 10 uM BTCC or PTCC conferred major resistance to apoptosis mediated by cisplatin (CP), an effective anti-neoplastic agent known to cause nephrotoxicity by damaging proximal tubular cells.