Response to Verd and Verd Re: “COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment”

To the Editor:

We thank Verd and Verd (7) for their thoughtful commentary, which raises two important points not covered in our article (1): (i) the widespread use of paracetamol (acetaminophen) in relation to glutathione availability in the general population and (ii) Down syndrome (DS) as particular risk factor for poor outcome and medical complications in COVID-19. The first is a specific example of a broader consideration worthy of further exploration in relation to redox imbalances and stress resilience, that is, the exposure of a complex biological system such as the human body to redox-active substances or glutathione-lowering conditions before becoming infected. Although DS is indeed associated with systemic oxidative stress, the concomitant mitochondrial and immune dysfunction as well as the metabolic, endocrine, and biochemical abnormalities [including alterations in micronutrient status, hydrogen sulfide production, and expression of numerous genes regulating mitochondrial/bioenergetic status (5)] suggests that the accompanying redox perturbations are not limited to changes in glutathione availability and utilization alone. How these alterations may affect the ability to achieve whole-body electron balance is unclear and deserves further study.

Paracetamol is the most widely used analgesic/antipyretic in the world. Although an abundance of literature exists on its hepatotoxicity after acute overdosing, in most countries this drug is available without prescription and used by millions of people without a second thought to control fever and mild-to-moderate pain. The majority of paracetamol is metabolized in the liver and safely excreted in the form of its glucuronide in the bile. A small proportion is metabolized through the cytochrome P450 pathway to form the highly reactive N-acetyl-p-benzoquinone imine, which is detoxified by conjugation with glutathione. Although this reaction is catalyzed by glutathione S-transferase, it is by no means specific for glutathione. As with all quinones (6), the reaction also occurs with protein thiols and other small aminothiols in a nonenzymatic manner (explaining the use of N-acetylcysteine in paracetamol intoxication and the protective role of glutathione in preventing protein adduct formation, mitochondrial dysfunction, and necrosis). Frequent paracetamol use represents a drain on the body's ability to maintain the availability of sufficient cysteine for the formation of glutathione and sulfate (SO₄ ²⁻) (conjugation to sulfate is an alternative pathway through which paracetamol is eliminated).

Similar considerations apply for provision of glutamine and glycine. As alluded to in our review, limitations in the availability of glycine to meet the body's demands are marked by increased urinary excretion of 5-l-oxoproline, a feature also observed with chronic paracetamol use. An increase in the demand for glycine is compounded by habitual aspirin use and ingestion of food preservatives such as benzoic acid, which require glycine conjugation for excretion (4). Chronic alcohol intake also lowers intracellular glutathione levels, thereby increasing paracetamol toxicity and sensitizing patients to pulmonary injury (3). Dietary selenium deficiency has similar effects (2).

Thus, a rather more complex picture emerges according to which oxygen, water, food, redox-active chemicals (including drugs and antioxidants), particulate matter, alcohol, and other lifestyle-related factors all impinge on redox regulation. Hence, what matters for human resilience against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other stressors is not simply determined by what is ingested or inhaled but also by how these substances can be handled by the body. The ability to cope with competing demands is determined by the extent to which the building blocks essential for cell/organ protection, function, adjustment, and healing can continue to be made available in sufficient quantities. To this end, dietary quality and nutrient status are fundamental determinants of the metabolic background against which all of these factors (including over-the-counter medications such as paracetamol) operate and either support or compromise the balanced functioning of the reactive species interactome.