title: The stress response of human proximal tubule cells to cadmium involves up-regulation of haemoxygenase 1 and metallothionein but not cytochrome P450 enzymes.
abstract: Enzymes of the cytochrome P450 (CYP) super-family are implicated in cadmium (Cd) -induced nephrotoxicity, however, direct evidence is lacking. This study investigated the endogenous expression of various CYP proteins together with the stress-response proteins, heme oxygenase-1 (HO-1) and metallothionein (MT) in human kidney sections and in cadmium-exposed primary cultures of human proximal tubular epithelial cells (PTC). By immunohistochemistry, the CYP members 2B6, 4A11 and 4F2 were prominently expressed in the cortical proximal tubular cells and to a lesser extent in distal tubular cells. Low levels of CYPs 2E1 and 3A4 were also detected. In PTC, in the absence of Cd, CYP2E1, CYP3A4, CYP4F2 and MT were expressed, but HO-1, CYP2B6 and CYP4A11 were not detected. A range of cadmium concentrations (0-100μM) were utilized to induce stress conditions. MT protein was further induced by as little as 0.5μM cadmium, reaching a 6-fold induction at 20μM, whereas for HO-1, a 5μM cadmium concentration was required for initial induction and at 20μM cadmium reached a 15-fold induction. The expression of CYP2E1, CYP3A4, and CYP4F2 were not altered by any cadmium concentrations tested at 48h. Cadmium caused a reduction in cell viability at concentrations above 10μM. In conclusion although cultured PTC, do express CYP proteins, (CYP2E1, CYP3A4, and CYP4F2), Cd-induced cell stress as indicted by induction of HO-1 and MT does not alter expression of these CYP proteins at 48h.
authors.affiliation: Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand; Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia.
authors.forename: Kanyarat
authors.initials: K
authors.lastname: Boonprasert
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia.
authors.forename: Soisungwan
authors.initials: S
authors.lastname: Satarug
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia.
authors.forename: Christudas
authors.initials: C
authors.lastname: Morais
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia.
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia; Department of Renal Medicine, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.
authors.forename: Kesara
authors.initials: K
authors.lastname: Na-Bangchang
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia; Department of Renal Medicine, Princess Alexandra Hospital, Brisbane, Australia. Electronic address: david.vesey@health.qld.gov.au.
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
mesh_terms: D002104:Cadmium / Q000633:toxicity*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D051547:Heme Oxygenase-1 / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects*; D008668:Metallothionein / Q000032:analysis*; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: D002104:Cadmium; D003577:Cytochrome P-450 Enzyme System; D008668:Metallothionein; D051547:Heme Oxygenase-1
keywords: Cadmium; Cytochrome P450 (CYP); Drug-metabolizing enzymes; HK2 cells; Heme oxygenase-1; Metallothionein; Proximal tubular cells; Stress response