GSH, a tripeptide of glutamic acid, cysteine, and glycine (GluCysGly), is the major water- soluble antioxidant in the cytoplasm, nuclei, and mitochondria of cells. Many of the critical antioxidant functions of GSH require GSH peroxidase, which exists in several forms. Reduction of oxidized GSH (GSH disulfide), which is produced by reactions involving GSH peroxidase, requires GSH reductase.
GSH is not transported into cells. For circulating GSH to increase intracellular GSH concen- trations, it must first be hydrolyzed to Glu and CysGly, which are subsequently transported into the cell and serve as substrates for GSH synthesis. Thus, GSH administered orally or parenterally, and that produced by the liver and released into the circulation enhance tissue levels of GSH by providing a source of its constituent amino acids. In contrast, GSH monoesters, which are well absorbed after oral administration, as is GSH, are readily transported to cells and then hydrolyzed to GSH and the corresponding alcohol. Thus, higher cellular levels of GSH result from oral administration of GSH monoesters than from oral administration of comparable doses of GSH.
GSH has been investigated for its protective effect against cisplatin-induced nephrotoxicity and peripheral neuropathy. Although oxidative damage most likely contributes to these toxicities, the protective effect of GSH can be accounted for by a chemical interaction between GSH and cisplatin instead of the antioxidant properties of GSH. GSH contains a thiol (sulfhydryl, an –SH moiety) group. Thiols are strongly nucleophilic and form stable covalent compounds with electrophilic compounds, such as the platinum coordination complexes cisplatin and carboplatin. Formation of the thiol–platinum complex inactivates the antineoplastic agent, which blocks not only its ROS- generating activity but also its cytotoxic effects. If inactivation occurs within the circulation before uptake of the drug by tumor cells, interference with the antineoplastic activity of cisplatin or carboplatin may occur. A similar concern exists if GSH is administered with alkylating agents, which are also strong electrophiles, because thiols can compete with DNA for alkylation, resulting in inhibition of antineoplastic activity. Thus, caution should be employed when GSH or any thiol compound is administered with platinum coordination complexes or alkylating agents.
Studies in laboratory animals have shown that intravenous administration of a high dose of GSH (up to 500 mg/kg) within 30 min of cisplatin injection protects against cisplatin-induced
neurotoxicity and nephrotoxicity. Subcutaneous injection of GSH or GSH monoisopropyl ester
2.5 h before injection of cisplatin also protected mice against nephrotoxicity and the acute lethal toxicity of cisplatin, although the GSH ester was far more effective than GSH itself. In these studies, treatment with GSH or GSH ester did not interfere with the antitumor effectiveness of cisplatin, which can be explained by the characteristics of uptake of GSH and cisplatin. GSH and cisplatin are cleared rapidly from the circulation.
Dietary Antioxidants 121 N-ACETYLCYSTEINE
N-Acetylcysteine (NAC) is well absorbed after oral administration and readily transported into cells, where it is deacetylated. Although NAC, a thiol compound, is a free-radical scavenger, its more important antioxidant role is providing an intracellular source of cysteine, a substrate for GSH synthesis. However, because of its nucleophilic thiol group, NAC (similar to GSH) can form stable covalent compounds with electrophilic alkylating agents and platinum coordination complexes, which inactivate the anticancer drugs. In this regard, NAC has been shown to block the cytotoxicity and ROS-generating capability of cisplatin in vitro. Thus, as with GSH, one should exercise caution when administering NAC during chemotherapy with any electrophilic antineoplastic agent.
In animal studies, NAC has been shown to prevent hemorrhagic cystitis that results from administration of cyclophosphamide or its position isomer ifosfamide. Hemorrhagic cystitis results from the toxic effect of acrolein, a metabolic product of cyclophosphamide or its position isomer ifosfamide. The mechanism whereby NAC prevents this toxicity may be prevention of the intra- cellular depletion of antioxidants, such as GSH, by acrolein. Concomitant administration of NAC with cyclophosphamide or ifosfamide does not impair antineoplastic activity, because both anti- cancer drugs are inactive until they are metabolized by the liver to their phosphoramide mustard
metabolites.
NAC (50 to 2000 mg/kg), by means of free-radical scavenging or by enhancing intracellular levels of GSH, protects mice against acute doxorubicin-induced cardiotoxicity without interfering with the antitumor activity of the drug.
GLUTAMINE
Glutamine is a conditionally essential amino acid. Although it does not possess antioxidant activity,
it serves as a source of glutamate for GSH synthesis, thus supporting cellular antioxidant systems. Because glutamine is a primary fuel source for the rapidly proliferating enterocytes of the gas- trointestinal tract, an important role of glutamine supplementation during chemotherapy is to reduce gastrointestinal injury that results from administration of antineoplastic drugs, especially the severe mucositis that results from treatment with antimetabolites such as 5-FU and methotrexate.
Glutamine has been shown to enhance the antitumor effectiveness of methotrexate in laboratory animals, an effect that may be attributed to the increase of the intracellular tumor concentration of methotrexate by glutamine. Oral glutamine, but not intravenous glutamine, has also been shown to reduce the bacteremia and mucosal injury associated with methotrexate-induced enterocolitis of rats. Glutamine, administered by intragastric infusion, accelerates healing of the gut mucosa in rats receiving 5-FU.
SELENIUM
Although inorganic selenium does not have antioxidant properties, selenium has an important role in cellular antioxidant defenses as a necessary component of selenoproteins. Selenium is incorporated into selenoproteins as selenocysteine. The glutathione (GSH) peroxidases are the best-characterized selenoproteins, although other circulating selenoproteins also have antioxidant functions.
In laboratory animals, parenteral administration of organic and inorganic selenium (210 to 12,000 μg/kg) has been shown to protect against cisplatin-induced nephrotoxicity. Protection occurs without apparent inhibition of the antineoplastic activity of cisplatin, although this may be attributed to the fact that selenium administration allows for higher doses of cisplatin to be used. Additionally, selenium administration reduces cisplatin-induced myelosuppression. This raises a concern similar to that with administering cisplatin with thiol compounds, i.e., that the reduction of myelosuppression may indicate that selenium can also interfere with the antitumor activity of cisplatin. Selenium, with chemical properties similar to those of sulfur, can bind with platinum and 7050_book.fm Page 121 Wednesday, July 12, 2006 3:27 PM
122 Pharmacodynamic Basis of Herbal Medicine
inactivate the antineoplastic platinum coordination complexes. Thus, caution should be used when administering selenium during chemotherapy with cisplatin and carboplatin.
Parenteral administration of 27 to 60 μg/kg of selenium to laboratory animals has been shown to inhibit doxorubicin-induced decreases in myocardial vitamin E and GSH peroxidase levels and to reduce changes in myocardial function that are consistent with acute doxorubicin-induced cardiotoxicity. Oral supplementation of sodium selenite also protects against acute doxorubicin- induced cardiotoxicity in rabbits.