Hydroquinone regulates hemeoxygenase-1 expression via modulation of Src kinase activity through thiolation of cysteine residues

The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous papers have addressed the potential role of HQ in tumorigenic responses, the immunosuppressive and anti-inflammatory effects of hydroquinone have also been considered. In this study, we characterized the mechanism of the induction of hemeoxygenase (HO)-1 and other phase 2 enzymes by HQ and its derivatives. HQ upregulated the mRNA and protein levels of HO-1 by increasing the antioxidant-response element-dependent transcriptional activation of Nrf-2. Src knockdown or deficiency induced via siRNA treatment and infection with a retrovirus expressing shRNA targeting Src, as well as exposure to PP2, a Src kinase inhibitor, strongly abrogated HO-1 expression. Interestingly, HQ directly targeted and bound to the sulfhydryl group of cysteine-483 (C483) and C400 residues of Src, potentially leading to disruption of intracellular disulfide bonds. Src kinase activity was dramatically enhanced by mutation of these cysteine sites, implying that these sites may play an important role in the regulation of Src kinase activity. Therefore, our data suggest that Src and, particularly, its C483 target site can be considered as prime molecular targets of the HQ-mediated induction of phase 2 enzymes, which is potentially linked to HO-1-mediated cellular responses such as immunosuppressive and anti-inflammatory actions.