Oxidation of Plasma Cysteine/Cystine and GSH/GSSG Redox Potentials by Acetaminophen and Sulfur Amino Acid Insufficiency in Humans

Abstract

Variations in plasma sulfur amino acid (SAA) pools are associated with disease risks, but little information is available about the factors affecting plasma SAA pools. Drug metabolism by glutathione (GSH) and sulfate conjugation can, in principle, represent a quantitatively important burden on SAA supply. The present study was designed to determine whether therapeutic doses of acetaminophen (APAP) alter SAA metabolism in healthy human adults. A double-blind, crossover design incorporating four treatment periods with diets providing 100% of the recommended dietary allowance (RDA) for SAA without or with APAP (15 mg/kg) and 0% RDA for SAA without or with APAP, in randomized order. After a 3-day equilibration period, chemically defined diets with 100 or 0% RDA for SAA were given for 2 complete days. On day 3, APAP or placebo was given in two successive doses (6-h interval), and timed plasma samples were collected. With SAA intake at 100% RDA, APAP administration oxidized the plasma cysteine/cystine redox potential (E h CySS) but not the plasma GSH/GSSG redox potential (E h GSSG). The extent of oxidation caused by APAP was similar to that seen with 0% SAA and no APAP. However, APAP administration with 0% SAA did not cause further oxidation beyond APAP or 0% SAA alone. In contrast, an oxidation of the plasma E h GSSG was apparent for SAA insufficiency only with APAP. The results suggest a need to evaluate possible effects of APAP in association with SAA insufficiency as a contributing factor in disease risk.

Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids

“…The increased excretion of dimethyl sulfone and methionine sulfoxide meant that oxidation of sulfur-containing compounds occurred, likely as a consequence of decreased antioxidant capacities of cysteine and GSH. This is supported by the observation that paracetamol treatment oxidized the plasma cysteine/ cystine redox potential in human (Mannery et al 2010). An increased oxidative stress could have clinical effect, since oxidative stress has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, other diseases, and also in senescence (Dröge 2002).…”

“…Kinetics measurements were not performed for ethical reasons: elderly subjects were suffering. In volunteers aged 18 to 40 years, baseline plasma cysteine, cystine, reduced and oxidized forms of GSH concentrations were unchanged after 2 day of paracetamol treatment at the dose of 1 g/day (Mannery et al 2010). Nevertheless, in the latter study some differences appeared significant at some time-points across the 12-h kinetics.…”

“…One single dose of paracetamol (2 g) decreases plasma cysteine and GSH concentrations (Burgunder et al 1989) and 1 g/day paracetamol oxidizes the plasma cysteine/cystine redox potential (Mannery et al 2010) in young adult men. Paracetamol induces dosedependent stimulations of rates of turnover of cysteine and glutathione in men (Lauterburg and Mitchell 1987).…”

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

“…We observed that an oxidized blood GSH E h was correlated with decreased blood SAH and plasma Hcys, which is consistent with an increase in Hcys flux through the transsulfuration pathway under oxidized intracellular conditions. 16 Although some studies have used plasma GSH E h as a marker of intracellular redox, 44,45 we did not observe significant correlations of Hcys or SAH with plasma GSH E h , which suggests that whole blood GSH E h might be a better indicator of the intracellular redox environment, at least within blood cells. However, an oxidized plasma GSH E h is thought to reflect oxidative stress in other tissues 46 or systemic oxidative stress 47 and is observed in aging, 48 obesity 49 and disease states such as asthma 50 and heart disease.…”

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

“…This can deplete cysteine stores (56,57). In addition, conjugation of acetaminophen to glutathione reduces its levels.…”