Prevention of Naphthalene-Induced Cataract and Hepatic Glutathione Loss by theL-Cysteine Prodrugs, MTCA and PTCA

Rathbun, William B.; Nagasawa, Hiromichi; Killen, Christina E.

doi:10.1006/exer.1996.0048

Cited by 33 publications

(26 citation statements)

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“…This was probably because erythrocytes retained more glutathione reductase and NADPH needed to replenish GSH and keep it at normal levels despite its depletion by metabolism [23] . There was a significantly low level of GSH in both plasma and lens in group D, which is generally consistent with the report of Rathbun et al [24] . GSH concentration in group F was significantly lower than in group D. This could either be the result of liver damage, which would result in reduced production of the enzymes required to regenerate GSH, or the result of increasing ROS levels due to high rates of metabolism of milk, or maybe both.…”

Section: Discussionsupporting

confidence: 82%

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Excessive Milk Intake as a Risk Factor, Probably Associated with Oxidative Stress, in Experimental Naphthalene-Initiated Cataract in Rats

Chen¹,

Jiang²,

Lu³

et al. 2011

Ophthalmic Res

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Aim: To determine whether a diet containing excessive amounts of milk aggravates naphthalene-initiated cataracts in a common animal model of age-related human cataract. Methods: Ninety Sprague-Dawley rats were fed a natural diet supplemented with either water (group A), normal amounts of milk (group B), excessive amounts of milk (group C), naphthalene plus water (group D), naphthalene plus normal amounts of milk (group E), naphthalene plus excessive amounts of milk (group F). Cataract development was monitored weekly using a slit lamp and lens gray value analysis. Concentrations of reactive oxygen species (ROS), reduced glutathione (GSH) and malondialdehyde (MDA) in rat lenses were measured to determine the role of oxidative stress in cataract induction. Results: By week 4, the cortical gray value was significantly higher in group F than that in group D, and the cortical gray value was significantly higher in group D than in group A. However, by week 8, no significant differences were observed among groups C, F, B, E and A. ROS concentrations in lenses of rats of groups C and F were slightly higher than in those of groups B, E and A, but ROS concentrations in group F were significantly higher than in the other groups receiving naphthalene (i.e. groups D and E). GSH concentrations in group F were significantly lower than in the other groups. MDA concentrations in group F were significantly higher than in the other groups receiving naphthalene, indicating increased lipid peroxidation induced by naphthalene plus excessive intake of milk. Conclusions: Our results provide quantitative evidence that excessive intake of milk aggravates naphthalene-initiated cataracts, which is probably due to oxidative damage caused by increased ROS.

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Section: Discussionsupporting

confidence: 82%

“…Accumulation of calcium in body tissues is a normal feature of the process of aging [24] , and such accumulation also occurs in the aging lens and cataract [16,27] . Total calcium level has been shown to be elevated in galactoseinduced cataract [3] .…”

Section: Discussionmentioning

confidence: 99%

Excessive Milk Intake as a Risk Factor, Probably Associated with Oxidative Stress, in Experimental Naphthalene-Initiated Cataract in Rats

Chen¹,

Jiang²,

Lu³

et al. 2011

Ophthalmic Res

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“…31 Other studies showed that PTCA significantly increased GSH biosynthesis in cultured rat lens compared with untreated controls 32 and prevented naphthalene-induced experimental cataracts in mice. 33 In this study, PTCA-treated mice had significantly normalized levels of inflammatory cytokines (IL-6 and IL-12), acute protein SAA, colon lesions, with higher levels of blood and hepatic GSH, and lower GSSG concentrations compared with other treated and untreated DSS animals. In addition, PTCA, like its 2-methyl analog, MTCA, 9 is expected to dissociate nonenzymatically to L-cyateine much more rapidly than RibCys, 34 hence, its efficacy in raising hepatic and plasma GSH levels.…”

Section: Discussionmentioning

confidence: 48%

Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model

Oz¹,

Chen²,

Nagasawa³

2007

Translational Research

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Oxidant-mediated injury plays an important role in the pathophysiology of inflammatory bowel disease (IBD). Recently, antioxidants were shown to modulate colitis in mice. In this study, the protective effects of L-cysteine and glutathione (GSH) prodrugs are further evaluated against progression of colitis in a murine model. ICR mice were fed compounds incorporated into chow as follows: Group (A) received chow supplemented with vehicle. Group (B) was provided 2-(RS)-npropylthiazolidine-4(R)-carboxylic-acid (PTCA), a cysteine prodrug. Group (C) received D-ribose-L-cysteine (RibCys), another cysteine prodrug that releases L-cysteine. Group (D) was fed Lcysteine-glutathione mixed sulfide (CySSG), a ubiquitous GSH derivative present in mammalian cells. After 3 days, the animals were further provided with normal drinking water or water supplemented with dextran sodium sulfate (DSS). Mice administered DSS developed severe colitis and suffered weight loss. Colonic lesions significantly improved in animals treated with PTCA and RibCys and, to a lesser extent, with CySSG therapy. Hepatic GSH levels were depleted in colitis animals (control vs DSS, P < 0.001), and normalized with prodrug therapies (control vs treatments, P > 0.05). Protein expressions of serum amyloid A and inflammatory cytokines [interleukin (IL)-6, IL-12, tumor necrosis factor-alpha (TNF-α), osteopontin (OPN)] were significantly increased in colitis animals and improved with therapies. Immunohistochemistry and Western blot analyses showed significant upregulation of the macrophage-specific markers, COX-2 and CD68, which suggests macrophage activation and infiltration in the colonic lamina propria in colitis animals. These abnormalities were attenuated in prodrug-treated mice. In conclusion, these data strongly support the novel action of the PTCA against colitis, which further supports a possible therapeutic application for IBD patients.Inflamed gut from ulcerative colitis and Crohn's disease patients is rich in activated macrophages and neutrophils. These inflammatory cells generate excess amounts of reactive oxygen species (ROS) with subsequent increased oxidative stress. 1 The increased generation of highly toxic ROS exceeds the limited intestinal antioxidant defense system, thereby contributing to intestinal oxidative injury in ulcerative colitis patients. 2 Excessive production of ROS has been demonstrated in circulating phagocytic and polymorphonu-clear leukocytes cells in inflammatory bowel disease (IBD) patients, using a chemiluminescence assay 3 and after stimulation with the bacterial chemotactic peptide, N-formyl-methionyl-leucylphenylalanine. 4 Thus, oxidant-mediated injury plays an important role in the pathophysiology of IBD. The endogenous tripeptide, glutathione (GSH), is the most important intracellular defense agent in mammalian organs, including the gut. GSH is involved in protein folding and protein synthesis as well as in intracellular signaling. 5 GSH may be depleted during inflammatory insults, and GSH-deficient mice show s...

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“…Notable, however, was the apparent poor efficacy displayed by the positive controls, MTCA and PTCA, compounds known to be highly effective in protecting mice against ACP-induced hepatotoxicity [4,25] as well as ACP- [26] and naphthalene-induced cataractogenesis [27]. This raised the question whether this pretreatment protocol, especially the use of CMC as vehicle for repeated injections, was problematical.…”

Section: Resultsmentioning

confidence: 97%

Double‐prodrugs of L‐cysteine: Differential protection against acetaminophen‐induced hepatotoxicity in mice

Crankshaw

Berkeley

Cohen

et al. 2002

J Biochem & Molecular Tox

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A series of double-prodrugs of L-cysteine, designed to release L-cysteine in vivo and stimulate the biosynthesis of glutathione (GSH), were synthesized. To evaluate the hepatoprotective effectiveness of these double-prodrugs, male Swiss-Webster mice were administered acetaminophen (ACP) (2.45 mmol/kg (360 mg/kg), intraperitoneally (i.p.)). Prodrug (2.50 mmol/kg, i.p. or 1.25 mmol/kg, i.p., depending on the protocol) was administered 1 h before ACP as a priming dose. A supplementary dose of prodrug (2.5 mmol/kg, i.p. or 1.25 mmol/kg, i.p. depending on the protocol) was administered 0.5 h after ACP. The plasma alanine amino transferase (ALT) values, 24 h after ACP administration were transformed to logs and the 95% and 99% confidence intervals of the log values were plotted and compared for each group. Hepatoprotection was assessed by the degree of attenuation of plasma ALT levels. With these multiple dose schedules, the use of 2% carboxymethylcellulose as vehicle for the prodrugs was found to be detrimental; therefore, the prodrugs were dissolved in dilute aqueous base and the pH adjusted for administration. When a priming dose was given 1 h before ACP followed by a supplementary dose 0.5 h after ACP, only N,S-bis-acetyl-L-cysteine, where both the sulfhydryl and amino groups of L-cysteine were functionalized with the acetyl group, was found to be effective in protecting mice against the hepatotoxic effects of ACP. This suggests that these acetyl groups were rapidly hydrolyzed in vivo to liberate L-cysteine. In contrast, N-acetylation of 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA) and its 2-n-propyl analog (PTCA), or N-acetylation of 2-oxothiazolidine-4-carboxylic acid (OTCA), reduced the hepatoprotective effects relative to the parent MTCA, PTCA, and OTCA, indicating that the release of L-cysteine in vivo from these N-acetylated thiazolidine prodrugs was metabolically unfavorable. The carbethoxy group, whether functionalized on the sulfhydryl or on the amino group of L-cysteine, or on the secondary amino group of MTCA, appears to be a poor "pro-moiety," since these carbethoxylated double-prodrugs of L-cysteine did not protect mice from ACP-induced hepatotoxicity.

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Prevention of Naphthalene-Induced Cataract and Hepatic Glutathione Loss by theL-Cysteine Prodrugs, MTCA and PTCA

Cited by 33 publications

References 0 publications

Excessive Milk Intake as a Risk Factor, Probably Associated with Oxidative Stress, in Experimental Naphthalene-Initiated Cataract in Rats

Excessive Milk Intake as a Risk Factor, Probably Associated with Oxidative Stress, in Experimental Naphthalene-Initiated Cataract in Rats

Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model

Double‐prodrugs of L‐cysteine: Differential protection against acetaminophen‐induced hepatotoxicity in mice

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