title: The immediate early genes, c-fos, c-jun and AP-1, are early markers of platinum analogue toxicity in human proximal tubular cell primary cultures.
abstract: These studies tested the hypothesis that c-fos, c-jun and AP-1 are early markers of platinum analogue-induced proximal tubule nephrotoxicity in primary rat proximal tubule (RPT) and human proximal tubule (HPT) cell cultures. The order of platinum analogue toxicity was cisplatin>transplatin>carboplatin in RPT and HPT cultures. Following a 2-h platinum analogue treatment, c-fos protein expression correlated with toxicity. Maximal c-fos protein levels were observed at 8-h (RPT) and 4-h (HPT) post-platinum analogue treatment. c-jun and AP-1 protein levels were maximal 4-h and 8-h, respectively, post cisplatin treatment in HPT cultures. In contrast, c-jun and AP-1 protein were not detected in RPT cultures. c-fos and c-jun mRNA levels were maximal at 60 and 120-min in RPT cell cultures, respectively, whilst c-fos and c-jun mRNA levels were maximal at 120-min in HPT cultures. Differences between HPT and RPT responses to cisplatin reveal inter-species differences associated with induction of c-fos and c-jun mRNA and protein, which in turn form the functional AP-1 complex prior to the onset of cellular toxicity. These studies highlight the utility of HPT cultures as an invitro model system, and the potential of c-fos and c-jun as early markers of nephrotoxicity to screen therapeutic lead compounds.
authors.affiliation: Department of Medicine and Therapeutics, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. rwainf@lsuhsc.edu
authors.forename: Richard David
authors.initials: RD
authors.lastname: Wainford
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weaver
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Hawksworth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C034697:transplatin; D016190:Carboplatin; D002945:Cisplatin