Glucuronidation hepatotoxicity

Hepatotoxicity from paracetamol overdose can occur with single doses as low as 10-15 g. The risk factors for hepatotoxicity in excessive doses include induction of cytochrome P450 enzymes malnutrition or fasting, due to reduced glutathione stores and reduced glucuronidation chronic alcohol use and age over five years [8, 13]. 

In each form of cholestasis, atypical bile adds, such as monohydroxy bile acids, aUo-bile adds, 1- or 6-hydroxylated bile acids and their sulphated or glucuronidated derivatives, are found in the sermn and/or urine. In cholestasis, the increase in the neosynthesis of atypical bile adds that pass into the kidney can be seen as a compensatory mechanism which eliminates potentially hepatotoxic bile acids by renal clearance. The highest renal excretion quota is demonstrated by tetrahydroxy bile acids. 

Clofibrate acyl glucuronide is an electrophilic metabolite that reacts with sulfhydryl groups and causes hepatotoxicity. 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

The primary route of valproic acid metabolism is /3-oxidation, although up to 40% of a dose may be excreted as the glucuronide. At least 10 metabolites of valproic acid have been identified. Some of these may have weak anticonvulsant activity, and at least one metabolite may be responsible for the hepatotoxicity reported with valproic acid. One of the lesser oxidative metabolites, 4-en-valproic acid, causes significant hepatotoxicity in rats. The formation of this metabolite is increased when valproic acid is given with enzyme-inducing drugs. ... 

Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites, contributing to the potential of valproate to cause hepatotoxicity, although this clinical outcome is rare. Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible. 

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

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