Paracetamol, oxidation

Blair, LA., Boobis, A.R., Davies, D.J. and Cresp, T.M. (1980). Paracetamol oxidation, synthesis and reactivity of N-acetyl-/>-benzoquinone imine. Tetrahedron Lett. 21, 4947-4950. 

Andreozzi R, Caprio V, Marotta R, Vogna D (2003) Paracetamol oxidation from aqueous solutions by means of ozonation and H2O2AJV system. Water Res 37 993-1004... 

Kinetics and Mechanism of Paracetamol Oxidation by Chromium(VI) in Absence and Presence of Manganese(II) and Sodium dodecyl Sulphate... 

The kinetics of paracetamol oxidation are first order each in [paracetamol] and [HCIOJ. The kinetic study shows that the oxidation proceeds in two steps. The effects of anionic micelles of sodiumdodecyl sulphate (SDS) and complexing agents (ethylenediammine tetraacetic acid (EDTA) arul2,2 -bi-pyridyl (bpy)) were also studied. Fast kinetic spectrophotometric method has been described for the determination of paracetamol. The method is based... 

This is used as a sulphydryl donor in the treatment of paracetamol poisoning. It has side effects of its own which include nausea, vomiting and drowsiness. It must be given early, otherwise it is ineffective since paracetamol oxidation to toxic metabolic products will already have occurred. In addition, cysteamine itself, or any sulphydryl donor, could precipitate hepatic coma in a patient with overt liver damage (21 ). 

The ammoximation reaction involves the in situ formation of hydroxylamine via TS-1 catalysed oxidation of NH3 with H2O2. Hence, there are no size restrictions with regard to the ketone substrate, because the reaction of NH2OH with the latter occurs in the bulk solution. For example, TS-1 catalyses the ammoximation of / -hydroxyacetophenone (Le Bars et al., 1996). Beckmann rearrangement of the oxime product (see Fig. 2.18) affords the analgesic paracetamol (4-acetaminophenol). 

Manno et al. [43] observed the formation of superoxide during the oxidation of arylamines by rat liver microsomes. Noda et al. [44] demonstrated that microsomes are able to oxidize hydrazine into a free radical. In contrast, hepatic cytochrome P-450 apparently oxidizes paracetamol (4 -hydroxyacetanilide) to A-acetyl-p-benzoquinone imine by a two-electron mechanism [45]. Younes [46] proposed that superoxide mediated the microsomal S -oxidation of thiobenzamide. 

After oral administration, paracetamol is completely absorbed from the gastrointestinal tract with peak plasma concentrations being reached in less than an hour. The drug is eliminated by conjugation with glucoronic acid in the liver. The chemical structure is liable to oxidation. 

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

Less potentially serious efforts may be produced by vegetables of the brassica family (cabbage, sprouts, spinach) which increase the activity of some oxidative enzymes, and possibly of conjugating (Phase II) enzymes also, leading to lowered Cp of some analgesics - notably paracetamol. 

The hydrolysis of some amides may be catalyzed by a liver microsomal carboxyl esterase, as is the case with phenacetin (Fig. 4.44). Hydrolysis of the acetylamino group, resulting in deacetylation, is known to be important in the toxicity of a number of compounds. For example, the deacetylated metabolites of phenacetin are thought to be responsible for its toxicity, the oxidation of hemoglobin to methemoglobin. This toxic effect occasionally occurs in subjects taking therapeutic doses of the drug and who have a deficiency in the normal pathway of metabolism of phenacetin to paracetamol. Consequently, more phenacetin is metabolized by deacetylation and subsequent oxidation to toxic metabolites (chap. 5, Fig. 24). 

The source of sulfate may be dietary or generated by oxidative metabolism of cysteine. PAPS can become depleted when large amounts of a foreign compound conjugated with sulfate, such as paracetamol, are administered. 

Metabolic activation. Although the kidney does not contain as much cytochromes P-450 as the liver, there is sufficient activity to be responsible for metabolic activation, and other oxidative enzymes such as those of the prostaglandin synthetase system are also present. Such metabolic activation may underlie the renal toxicity of chloroform and paracetamol (see chap. 7). Other enzymes such as C-S lyase and GSH transferase may also be involved in the activation of compounds such as hexachlorobutadiene (see chap. 7). In some cases, hepatic metabolism may be involved followed by transport to the kidney and subsequent toxicity. 

The role of GSH in cellular protection (see below) means that if depleted of GSH, the cell is more vulnerable to toxic compounds. However, GSH is compartmentalized, and this compartmentalization exerts an influence on the relationship between GSH depletion or oxidation and injury. The loss of reduced GSH from the cell leaves other thiol groups, such as those in critical proteins, vulnerable to attack with subsequent oxidation, cross-linking, and formation of mixed disulfides or covalent adducts. The sulfydryl groups of proteins seem to be the most susceptible nucleophilic targets for attack, as shown by studies with paracetamol (see chap. 7), and are often crucial to the function of enzymes. Consequently, modification of thiol groups of enzyme proteins, such as by mercury and other heavy metals, often leads to inhibition of the enzyme function. Such enzymes may have critical endogenous roles such as the regulation of ion concentrations, active transport, or mitochondrial metabolism. There is... 

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

However, the reactive metabolite will cause other changes as well as binding to protein. Thus, NAPQI will react both chemically and enzymatically with GSH to form a conjugate and will also oxidize it to GSSG and in turn be reduced back to paracetamol. This cyclical process may explain the occurrence of extensive depletion of GSH. NADPH will also reduce NAPQI and in turn be oxidized to NADP, although reduction via GSH is probably preferential. NADPH oxidation may also result from GSSG reduction via GSH peroxidase (Fig. 7.18). 

Analogues of paracetamol, which are unable to undergo covalent binding to protein, are still hepatotoxic and can undergo a redox reaction with GSH. However, oxidative stress has not been demonstrated in vivo, and there are differences between in vivo data and that obtained in isolated hepatocytes. 

The depletion of GSH and NADPH will allow the oxidation of protein sulfydryl groups, which may be an important step in the toxicity. Thus, GSH and protein sulfydryl groups, such as those on Ca2+-transporting proteins, are important for the maintenance of intracellular calcium homeostasis. Thus, paracetamol and NAPQI cause an increase in cytosolic calcium, and paracetamol inhibits the Na+/K+ ATPase pump in isolated hepatocytes. 

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