Renal and hepatic output of glutathione in plasma and whole blood

Dass, P. D.; Bermes, Edward W.; Holmes, Earle W.

doi:10.1016/0304-4165(92)90102-z

Cited by 51 publications

(25 citation statements)

References 18 publications

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“…In rats, total net hepatic output of glutathione in whole blood is, on the average, 20-fold greater than the output in plasma. 23 We found that glutathione in plasma and in whole blood responded differently in patients undergoing surgical trauma. The concentrations ofGSH in plasma decreased slightly, whereas the whole blood concentrations ofGSH remained unaltered ( Table 2).…”

Section: Discussionmentioning

confidence: 81%

Skeletal Muscle Glutathione After Surgical Trauma

et al. 1996

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ObjectiveThe authors investigate the effect of surgical trauma on skeletal muscle concentrations of glutathione in patients undergoing selective abdominal surgery. Summary Background DataThe posttraumatic state is accompanied by characteristic changes in the pattern of free amino acids and a decline of protein synthesis in human skeletal muscle. Glutathione has multiple metabolic functions that are involved in cellular homeostasis. It is unknown how surgical trauma affects the glutathione metabolism of skeletal muscle in surgical patients. MethodsEight patients undergoing elective abdominal surgery were investigated. Percutaneous muscle biopsies and blood samples were taken before operation and at 6, 24, and 48 hours after operation. The concentrations of glutathione were determined in muscle tissue, plasma, and whole blood, as well as the concentrations of the related amino acids in muscle and plasma. ResultsIn skeletal muscle, the levels of both reduced and total glutathione decreased by 40% (p < 0.01) at 24 hours and remained low at 48 hours after operation compared with the preoperative values. The glutathione concentration in plasma was 20% lower after operation compared with the concentration before operation (p < 0.05). There were no changes at the whole blood levels of glutathione. Tissue glutamate and glutamine decreased significantly after operation (p < 0.001), whereas intracellular cysteine and glycine remained unchanged. ConclusionsSkeletal muscle glutathione deficiency occurs after surgical trauma. This may lead to an increase in the susceptibility to intracellular oxidative injury. 420

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Section: Discussionmentioning

confidence: 81%

Skeletal Muscle Glutathione After Surgical Trauma

et al. 1996

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“…The observed sharp decline near that dose would, however, be explained if GSH in circulating blood-which is continuously extracted as a cysteine source by the kidney (Dass et al, 1992;Lash, 2005)-were proportional to GSH in liver, such that whenever GSH in liver (and consequently, in blood) becomes depleted below a critical threshold fraction f, cysteine extraction by the kidney becomes sharply reduced. In the WQSM model, this assumption is reflected for x = kidney by setting W x = 5[R x (t)/f] -n x for all [R x (t)] -1 < f, and W x = 1 otherwise, with f = 40%.…”

Section: A B C D E F G Hmentioning

confidence: 99%

“…While all active mammalian cells use GSH to bind oxidative products of mitochondrial and cytosolic metabolism, key metabolizing tissues (including liver, kidney, lung and intestine) synthesize and maintain comparatively high GSH concentrations, with liver being a primary source of GSH exported in systemically circulating blood (in which 98% of the GSH is contained in red blood cells), from which GSH is transported to and extracted by other organsprincipally in the kidney-as a primary source of cysteine used for (e.g., GGS-mediated) intracellular GSH resynthesis (Dass et al, 1992;Lohr, 1998;Lash, 2005). The kidney is among mammalian tissue types that express the greatest levels of GST-specific mRNA, reflecting relatively high GSH turnover in these tissues as one of the key mechanisms cells use to effectively inhibit oxidative stress that may arise from a variety of normal and pathological processes (Estonius et al, 1999;Forsberg et al, 2001).…”

Section: A B C D E F G Hmentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rattumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding "uncertainty" factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption.This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.3

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“…While all active mammalian cells use GSH to bind oxidative products of mitochondrial and cytosolic metabolism, key metabolizing tissues (including liver, kidney, lung and intestine) synthesize and maintain comparatively high GSH concentrations, with liver being a primary source of GSH exported in systemically circulating blood (in which 98% of the GSH is contained in red blood cells), from which GSH is transported to and extracted by other organs-principally in the kidney-as a primary source of cysteine used for (e.g., GGSmediated) intracellular GSH resynthesis (Dass et al, 1992;Lohr, 1998;Lash, 2005). The kidney is among mammalian tissue types that express the greatest levels of GST-specific mRNA, reflecting relatively high GSH turnover in these tissues as one of the key mechanisms cells use to effectively inhibit oxidative stress that may arise from a variety of normal and pathological processes (Estonius et al, 1999;Forsberg et al, 2001).…”

Section: Xmentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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A relatively simple, quantitative approach is proposed to address a specific, important gap in the approach recommended by the USEPA Guidelines for Cancer Risk Assessment to address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen.Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone.Bound-specific "adjustment" factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound.3

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Renal and hepatic output of glutathione in plasma and whole blood

Cited by 51 publications

References 18 publications

Skeletal Muscle Glutathione After Surgical Trauma

Skeletal Muscle Glutathione After Surgical Trauma

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

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