Cytochrome P450 liver enzymes metabolism

Metabolism and drug-drug interaction issues are discovered by screening for inhibition and induction of cytochrome P450 liver enzymes (CYP450). FDA guidelines have specific recommendation for substrates (Table 7.2) and inhibitors (Table 7.3) to be nsed in these assays. 

The BZs are all metabolized in the liver via the hepatic cytochrome P450 (CYP) enzymes through one or both of the following pathways phase I oxidation and dealkylation, and/or phase II conjugation to glucuron-ides, sulfates, and acetylated compounds. Diazepam, chlordiazepoxide, and flurazepam all undergo both phase 1 and phase 11 metabolism. Lorazepam, lorme-tazepam, oxazepam, and temazepam are all metabolized by phase 11 alone and are better tolerated by patients with liver impairment. 

Cytochrome P450 Liver In vitro Enzyme inhibition effects on drug metabolism... 

Cholecalciferol 25-hydroxylase is not restricted to the liver kidneys, skin, and gut microsomes also have a cytochrome P450 -dependent enzyme that catalyzes the 25-hydroxylation of cholecalciferol and la-hydroxycholecalciferol, hut not ergocalciferol. Although there is some evidence that calcitriol can reduce the activity of calciferol 25-hydroxylase, it is not known whether this is physiologically important the major factor controlling 25-hydroxylation is the rate of uptake of cholecalciferol into the liver. It is the fate of calcidiol in the kidneys that provides the most important regulation of vitamin D metabolism (Wikvall, 2001). 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Although the role of cytochrome P450 in the metabolism of carbofuran has not been explored in any system, the metabolism of ethyl carbamate by P450 2EI has been reported by Lee elal. (1998). The study implicated cytochrome P450 2EI and carboxylcsterase enzyme in the metabolism of carcinogens such as ethyl carbamate in the murine liver microsomal system. The fish taken from a lake in Newfoundland with a history of hydrocarbon pollution showed increased AHH activity (Payne and Penrose, 1975). Thus, many workers have studied the EROD activity of fish in laboratory conditions or naturally exposed samples as a molecular biomarker for aquatic pollution. These studies are reviewed by Whyte etal. (2000) and Goldfarb el al. (1998), In addition, EROD activity in carbofuran-lreated fish has been measured in laboratory conditions. 

The toxieity of triehloroethylene is dependent upon metabolism and induction of cytochrome P450. Triehloroethylene is metabolized through chloral hydrate to compounds including trichloroacetic acid and dichloroacetic acid which alter intercellular communication, induce peroxisome proliferation and may promote tumor production. Significant variability in trichloroethylene metabolism in 23 human haptic microsomal samples was reported by Lipscomb et al. It was also demonstrated that the trichloroethylene metabolism is dependent on enzymatic activities of the cytochrome system, and they conclude that their data indicates that humans are not uniform in their capacity for CPY dependent metabolism of trichloroethylene and increased activity may increase susceptibility to trichloroethylene induced toxicity in humans. These observations are compatible with the variability reaction which is depending on nutritional factors, enzyme induction factors, hormonal factors and interaction with other environmental chemicals, prescription medications and general health conditions, and explains the variable reports as far as trichloroethylene and level of liver toxicity in the various individuals studied. 

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