The following figure shows the metabolism of the drug acetaminophen (commonly kn

Question

The following figure shows the metabolism of the drug acetaminophen (commonly known as paracetamol). A minor pathway of metabolism is the CYP-mediated formation of the toxic product NAPQI which is subsequently inactivated by glutathione conjugation.

a. What effect would you expect ethanol consumption (which upregulates CYP2E1 expression) to have on acetaminophen metabolism?

b. Glucuronyl transferase catalyses the conjugation of acetaminophen to glucuronic acid. What effect would you expect from a deficiency in this enzyme?

Explanation / Answer

A....many reports claiming that the hepatotoxicity of paracetamol (acetaminophen) is increased in chronic alcoholics, and that such individuals not only carry an increased risk of severe and fatal liver damage after acute overdosagebut that similar serious liver damage may also occur with ‘therapeutic’ use In the original studies of the mechanisms of toxicity, paracetamol was found to cause liver damage through conversion by hepatic cytochrome P450 enzymes to a minor but toxic intermediate metabolite and this was subsequently identified as N-acetyl-p-benzoquinoneimine In accordance with this mechanism, the susceptibility to paracetamol-induced liver damage in animals was increased when these enzymes were stimulated by prior administration of inducing agents such as phenobarbitone and 3-methylcholanthrene, and decreased by inhibitors such as piperonyl butoxide and 4-methylpyrazole .Chronic administration of ethanol also causes microsomal enzyme induction in animals and as expected, this increased the metabolic activation and the hepatotoxicity of paracetamol In the circumstances, it was natural to suspect that there might be similar potentiation of paracetamol hepatotoxicity following overdosage in chronic alcoholics and indeed, this had been suggested in an early study in which the outcome of severe paracetamol poisoning in potentially induced patients appeared to be worse than in similar noninduced patients Subsequently, many anecdotal reports appeared describing severe and sometimes fatal liver damage in chronic alcoholics taking paracetamol in overdosage as well as after its use for therapeutic purposes

The collective weight of these uncontrolled case reports has been taken uncritically as ‘proof’ that the hepatotoxicity of paracetamol is increased in chronic alcoholics and it is universally assumed that as in animals, the mechanism is increased production of the toxic metabolite caused by induction of hepatic drug metabolizing enzymes. These beliefs were strengthened further by the demonstration in animals that the primary isoform of cytochrome P450 which is induced by ethanol (CYP2E1) is also involved in the metabolic activation of paracetamol Potentiation of paracetamol hepatotoxicity by chronic consumption of ethanol in man is now accepted as established truth and it has been referred to as a ‘classic syndrome of medicine’ As this review will show, however, there is insufficient evidence to justify the claims made for such an interaction in man.

B...glucorinidation is a major pathway of xenobiotic biotransformation in most mammalian species, and requires the cofactor uridine diphosphate-glucuronic acid., The reaction is metabolized by UGTs (also called glucuronyltransferases), which are present in many tissues., The site of glucorinidation is generally an electron-rich nucleophilic heteroatom (oxygen, nitrogen, or sulfur). Human UGTs are a family of enzymes that detoxify many hundreds of compounds by their conjugation to glucuronic acid, rendering them harmless, more water-soluble, and, hence, excretable. Genetic inheritance, age, and environmental factors largely determine the different profiles of the inducible hepatic UGTs. Variation in the complement of these ugts may result in dramatic differences in the safe elimination of toxic metabolites.

UDP-glucuronosyl transferases, is part of the metabolic clearance mechanism for steroid hormones by the liver and extrahepatic tissues. There are 18 known UDP-glucuronosyl transferases that have been divided into three subfamilies

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