p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling

The aryl hydrocarbon receptor (AhR), a client protein of heat shock protein 90 (Hsp90), is a ligand-activated transcription factor that plays a role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. Tobacco smoke activates AhR signaling leading to increased transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to mutagens. Recently, p53 was found to regulate Hsp90 ATPase activity via effects on activator of Hsp90 ATPase (Aha1). It is possible, therefore, that AhR-dependent expression of CYP1A1 and CYP1B1 might be affected by p53 status. The main objective of this study was to determine whether p53 modulated AhR-dependent gene expression and PAH metabolism. Here, we show that silencing p53 led to elevated Aha1 levels, increased Hsp90 ATPase activity, and enhanced CYP1A1 and CYP1B1 expression. Overexpression of wild-type p53 suppressed levels of CYP1A1 and CYP1B1. The significance of Aha1 in mediating these p53-dependent effects was determined. Silencing of Aha1 led to reduced Hsp90 ATPase activity and downregulation of CYP1A1 and CYP1B1. In contrast, overexpressing Aha1 was associated with increased Hsp90 ATPase activity and elevated levels of CYP1A1 and CYP1B1. Using p53 heterozygous mutant epithelial cells from patients with Li-Fraumeni syndrome, we show that monoallelic mutation of p53 was associated with elevated levels of CYP1A1 and CYP1B1 under both basal conditions and following treatment with benzo[a]pyrene. Treatment with CP-31398, a p53 rescue compound, suppressed benzo[a]pyrene-mediated induction of CYP1A1 and CYP1B1 and the formation of DNA adducts. Collectively, our results suggest that p53 affects AhR-dependent gene expression, PAH metabolism, and possibly carcinogenesis

Uptake and metabolism of cisplatin by rat kidney

Uptake and metabolism of cisplatin by rat kidney. Cisplatin, an effective antineoplastic agent, is toxic to the kidney. Since the kidney's vulnerability to cisplatin may originate in its ability to accumulate and retain platinum to a greater degree than other organs, we studied the characteristics of the renal accumulation of platinum and investigated the nature of intracellular platinum. Cisplatin and ethylenediammine-dichloroplatinum, nephrotoxic and antineoplastic liganded platinum compounds, were concentrated in rat renal cortical slices fivefold above medium concentration. Platinum uptake was energy- and temperature-dependent and could be inhibited by drugs which inhibit base transport. The organic anions para-aminohippurate and pyrazinoate did not reduce renal slice platinum uptake. Unbound platinum in the blood and urine was predominantly cisplatin but unbound platinum in kidney cytosol was not. This latter compound, in contrast to cisplatin, was not active as a mutagen. These studies suggest that the kidney accumulates platinum in part by transport or specific binding to the base transport system in the kidney and biotransforms it intracellularly. Unbound platinum in the cell is not cisplatin and may no longer be toxic.Captation et métabolisme du cisplatine par le rein de rat. Le cisplatine, un agent anti-néoplasique efficace, est toxique pour le rein. Puisque la vulnérabilité du rein au cisplatine pourrait provenir de sa capacité d'accumuler et de conserver le platine à un degré plus élevé que d'autres organes, nous avons étudié les caractéristiques de l'accumulation rénale de platine et cherché la nature du platine intra-cellulaire. Le cisplatine et l'éthylènediamminedichloroplatine, des composés néphro-toxiques et anti-néoplasiques liés au platine, étaient concentrés dans des tranches corticales rénales de rat cinq fois plus que la concentration du milieu. La captation du platine était dépendante de l'énergie et de la température, et pouvait être inhibée par des médicaments qui inhibent le transport des bases. Les anions organiques para-aminohippurate et pyrazinoate ne diminuaient pas la captation du platine par les tranches rénales. Le platine non lié dans le sang et l'urine était de façon prédominante du cisplatine, mais le platine non lié dans le cytosol de rein n'en était pas. Ce dernier composé, contrairement au cisplatine, n'était pas actif en tant que mutagène. Ces études suggèrent que le rein accumule le platine en partie par un transport ou par une liaison spécifique au système de transport des bases dans le rein, et le biotransforme dans les cellules. Le platine non lié dans la cellule n'est pas du cisplatine et pourrait ne plus être toxique