IN THIS ISSUE pubs.acs.org/crt
Special Features Chromium is a contaminant in drinking water supplies in many geographic areas, leading to concern because Cr(VI) is a known carcinogen. Now, Zhitkovich (DOI 10.1021/tx200251t) provides an enlightening review of the human and natural sources of chromium contamination in drinking water and what we know about the cancer threat arising from this contamination. Differential toxicity is the foundation for most cancer chemotherapeutic agents. One mechanism of differential toxicity that has become a focus of recent cancer chemotherapeutic discovery is the stimulation of death receptors. Progress in this area is reviewed by Muntane (DOI 10.1021/tx2002349) who explains how selective targeting of death receptors may increase the efficacy of traditional cancer chemotherapeutics.
Mixed Phase System to Study Vapor Toxicity
Toluene diisocyanate (TDI), a compound used for making polyurethane foam, is both a direct toxicant and a respiratory sensitizer. TDI exposure leads to decreased cellular thiol levels, and allergic sensitivity to TDI is correlated with specific GSH S-transferase polymorphisms. These observations suggest a role for GSH in TDI toxicity. Most prior studies to evaluate this role have been carried out in aqueous solution despite TDI’s aqueous insolubility and its tendency to self-aggregate in and react with water. To avoid these complications and to better reproduce the physiological conditions of TDI exposure, Wisnewski et al. (DOI 10.1021/tx2002433) explored a mixed phase system. Wisnewski et al. exposed aqueous solutions of GSH to TDI vapor. HPLC followed by MS analysis of the resulting reaction mixtures revealed the formation of two mono(GSH)-TDI adducts and two bis(GSH)-TDI adducts. Subsequent incubation of these adducts with human serum albumin led to transfer of TDI to 8 different lysine residues on the protein, and concomitant changes in protein charge and/or conformation as indicated by a shift in electrophoretic mobility. The pattern of adduction was distinct from that observed after direct incubation of albumin with aqueous TDI. These results support the hypothesis that reaction with GSH to form adducts may stabilize TDI for delivery to other sites. There, transfer of TDI from GSH to reactive centers on proteins or other macromolecules may lead to damage and/or antigenicity. The findings further support the value of a mixed phase system to explore the reactivity of gas phase toxicants. r 2011 American Chemical Society
L-DOPA:
Friend or Foe?
Parkinson’s disease (PD), the second most common neurodegenerative disease in the United States, is characterized by distinctive movement abnormalities and, ultimately, dementia. The disease is caused by the loss of dopaminergic neurons in the substantia nigra region of the brain, a process that is caused, at least in part, by oxidative damage. Thus, the fact that the primary drug used to treat PD, L-DOPA, is itself a pro-oxidant leads to concern that it may actually facilitate disease progression. The recent finding that L -DOPA causes decreased activity of both thioredoxin (Trx1) and glutaredoxin (Grx1) and induces apoptosis in SHSY5Y neuronal cells led Sabens et al. (DOI 10.1021/tx200082h) to explore the neuronal toxicity of L-DOPA in greater detail. ASK1 is a mitogen-activated protein kinase kinase kinase (MAPKKK) known to mediate apoptosis and to be regulated by Grx1 and Trx1. ASK1 activation leads to activation of the terminal MAPKs p38 and JNK. Sabens et al. found that selective inhibitors of either p38 or JNK protected SHSY5Y cells from L-DOPA toxicity and that the inhibitors together had a synergistic effect. Similarly, siRNA-mediated knockdown of ASK1 expression exerted a protective effect against L-DOPA that was proportional to the degree of ASK1 protein reduction. In contrast, an inhibitor of MLK, another MAPKKK that can regulate p38 and JNK, had no effect on L-DOPA-mediated apoptosis in the neuronal cells, and L-DOPA treatment had no effect on the activity of the Grx1/Trx1regulated transcription factor NF-kB. Together, the results strongly Published: October 17, 2011 1597
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Chemical Research in Toxicology suggest that apoptosis resulting from L-DOPA exposure is mediated by ASK1 and its downstream effectors p38 and JNK. Thus, inhibitors of this pathway may help to delay disease progression in PD patients being treated with L-DOPA.
Death by Mitochondrial Inhibition
IN THIS ISSUE
oxidoreductase activity from all species. However, TMC2O exhibited a distinct selectivity (3-fold) for the L. tarentolae enzyme over that from bovine heart. Esterification of TMC2O to yield TMC2OE005 improved the potency of the compound and increased its selectivity for L. tarentolae to 12-fold. These results confirm that some chromanols possess selective toxicity against leishmania. In the case of TMC2O, the toxic mechanism includes inhibition of the cyt bc1 complex. Further investigation to exploit this differential toxicity could lead to much needed new antileishmanial drugs.
Differential toxicity is the foundation for the majority of our antimicrobial agents. One potential target for the discovery of new antimicrobials is the mitochondrion. For example, the naphthoquinone atovaquone (ATQ), which selectively inhibits the cytochrome bc1 (cyt bc1) complex of the pathogenic protozoans Pneumocystis carinii and Toxoplasma gondii, was approved for use against these organisms in 1994. In an effort to identify new selective mitochondrial inhibitors, Monzote et al. (DOI 10.1021/tx200233c) investigated a series of chromanol derivatives.
Although chromanols (including vitamin E) are well-known for their antioxidant properties, it is clear that they exert biological effects through other mechanisms. Monzote et al. chose the chromanols Twin, TMC2O, and TMC4O (see figure) because of their structural similarity to stigmatellin (Stig), a compound known to inhibit the mammalian cyt bc1 complex. They tested the toxicity of these compounds against the parasitic protozoan Leishmania amazonensis and macrophages, the cells that leishmania infect in the vertebrate host. They found that the chromanols were more selectively toxic against L. amazonensis than ATQ or pentamidine, a currently used antileishmanial drug. To determine if the toxicity of the chromanols was due to the inhibition of mitochondrial function, Monzote et al. tested the compounds’ effects on the decylubiquinol/cyt c3+ oxidoreductase activity in mitochondrial fractions from yeast, bovine heart, and Leishmania tarentolae. Stig and ATQ, the most potent of the compounds tested, showed some degree of selectivity against the enzymatic activity in yeast versus bovine heart. The chromanols were all substantially less potent than Stig or ATQ against the 1598
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