Sulfate conjugation in drug metabolism: role of inorganic sulfate.

Federation proceedings 08/1986; 45(8):2235-40.
Source: PubMed

ABSTRACT Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract 1. Ethanol consumption is known to be linked in varying degrees to numerous ailments including damage to the nervous, endocrine and musculoskeletal systems and the gastrointestinal tract as well as extensive liver injury and several cancerous events. 2. Although acetaldehyde is the presently favoured candidate, both directly and indirectly, for such deleterious outcomes, over the years many other mechanisms and suggestions have been advanced. 3. The sparse literature concerning ethyl sulphate, a recently confirmed human metabolite of ethanol, has been examined, evaluated and interpreted to put forward the new proposition that ethyl sulphate itself may be able to alkylate various biological macromolecules thereby leading to toxicity.
    Xenobiotica 07/2014; · 2.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.
    Critical Reviews in Toxicology 02/1992; 22(5-6):371-89. · 6.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic Fatigue/Immune Dysfunction Syndrome (CFIDS), a condition characterized by disabling fatigue, is difficult to manage clinically due to its diverse symptomatology. This study investigated use of a hepatic detoxification supplement and elimination diet in 14 CFIDS patients with compromised detoxification status, as assessed by caffeine clearance (phase I CYP1A2) and benzoate conversion (phase II glycine conjugation) assays. After intervention, most subjects reported a decrease in symptoms. Moreover, subjects who initially displayed the highest ratio of CYP1A2 to benzoate conversion showed statistically significant (p
    Journal of Advancement in Medicine 11/1998; 11(4):247-262.