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Neuroprotective role of Withania somnifera root extract in maneb-paraquat induced mouse model of parkinsonism

To replenish intracellular GSH, cells synthesize GSH in a two-step metabolic pathway centred on the rate-limiting enzyme glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a regulatory or modifier (GCLM) subunit, and the GSH synthetase (GS) 22

Acetaminophen in doses above 2g/day (saturates sulfation and glucuronidation, depletes glutathione catastrophically) R Alcohol (depletes glutathione, NAD+, SAM-e, and directly damages hepatocytes) R Charcoal-grilled meats (heterocyclic amines that undergo bioactivation via sulfation and acetylation, generating DNA-reactive intermediates) R Chronic NSAID use (competes for glucuronidation and amino acid conjugation pathways) Excess fructose (depletes ATP and drives uric acid production, impairing energy-dependent conjugation) R Glyphosate residues on non-organic produce (disrupts glycine metabolism and chelates manganese) R High-dose turmeric or quercetin without cycling (both inhibit SULT1A1 and can paradoxically impair sulfation at high sustained doses) R Processed foods with benzoate preservatives (benzoic acid consumes glycine through conjugation, depleting the glycine pool for other Phase II reactions) R Proton pump inhibitors chronically (reduce magnesium absorption, impair glucuronidation) R Testing These tests can help identify which conjugation pathways are impaired and what is contributing to the dysfunction

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