Dietary supplementation with cysteine prevents adverse metabolic outcomes of repeated cures with paracetamol in old rats

Abstract

Cysteine (Cys), a conditionally indispensable amino acid, is required for the detoxification of paracetamol (acetaminophen, N-acetyl-para-aminophenol, 4-hydroxy-acetanilide, APAP), a drug of widespread use in older persons. We recently reported that repeated APAP cures could worsen sarcopenia in old rats, likely to be due to the impairment of Cys/GSH homoeostasis. The aim of the study was to evaluate whether a dietary Cys supplementation during APAP cures could improve Cys/GSH homoeostasis and thus preserve skeletal muscle. Male 21·5-month-old Wistar rats received three 2-week-long cures of APAP (1 % of diet) alone or with extra Cys (0·5 % of diet), intercalated with washout periods of 2 weeks (APAP and APAP-Cys groups, respectively). They were compared with untreated control rats (CT group). CT and APAP-Cys groups were pair-fed to the APAP group. Dietary Cys supplementation was efficient to prevent increase in liver mass (P<0·0001), decrease in liver GSH (P<0·0001), increase in blood GSH concentration (P<0·0001), and to some extent, decrease in plasma free Cys concentration (P<0·05), all induced by repeated APAP cures. The addition of Cys to APAP cures decreased plasma alanine transaminase (P<0·05), the fractional synthesis rate of liver proteins (P<0·01), and increased masses of extensor digitorum longus (P<0·01), and soleus (P<0·05), compared with the APAP group. Cys supplementation prevented alteration in Cys/GSH homoeostasis and increased some muscle masses in old rats under repeated cures with a non-toxic dose of APAP.

Plant Protein Can Be as Efficient as Milk Protein to Maintain Fat Free Mass in Old Rats, Even When Fat and Sugar Intakes Are High

“…Another strategy would be to mitigate oxidative stress, inflammation, and insulin resistance that increase during aging (9,27). Because of its presence in glutathione, cysteine can help to prevent the alteration of the redox status observed during aging (18,19), while long-term supplementation with cysteine was shown to delay loss of muscle mass in aging (20). This was the rationale for designing a protein blend with relatively high amounts of leucine, arginine and cysteine contents and testing its effect in both standard and high fat high sucrose diets.…”

“…This redox status is altered with aging (18). The requirement for cysteine seems to increase with aging because of changes in metabolic demand in relation with oxidative stress, low grade inflammation, and increased medication use (19). In line with this, long-term supplementation with cysteine was shown to delay loss of muscle mass in aging (20,21).…”

Activation of the eIF2α-ATF4 Pathway by Chronic Paracetamol Treatment Is Prevented by Dietary Supplementation with Cysteine

“…Dietary supplementation with Cys has been shown to reduce the deleterious effects of chronic treatment with APAP [20]. To explore the role of Cys deficiency in upregulating the eIF2α-ATF4 pathway, Ctrl and APAP diets were both supplemented with 0.5% Cys or 0.37% alanine so that the four diets were iso-nitrogenous (Figure 6A).…”

“…To study the effect of the dietary supplementation with Cys on the response to APAP treatment, the Ctrl diet and APAP diet were supplemented with 0.5% L-cysteine (Cys diet and APAP-Cys diet, respectively). The Cys supplement aimed to cover the extra need of Cys needed to detoxify APAP [20]. The Ctrl and APAP diets were supplemented with L-alanine (0.37%) to make them iso-nitrogenous to Cys diet and APAP-Cys diet (Ala diet and APAP-Ala diet, respectively).…”