Liver protein oxidation

The effects of antioxidants on protein oxidation were also studied in animal experiments. Barja et al. [73] demonstrated that feeding guinea pigs with vitamin C decreased endogenous protein oxidative damage in the liver. Administration of the mixture of antioxidants containing Trolox C, ascorbic palmitate, acetylcysteine, (3-carotene, ubiquinones 9 and 10, and (+)-catechin in addition to vitamin E and selenium to rats inhibited heme protein oxidation of kidney homogenates more efficiently than vitamin E + selenium [74]. 

On the other hand, in rats, a single dose of 6,156 mg/kg hexachloroethane in mineral oil had no effects on a different set of biochemical indicators of liver function (microsomal protein, oxidative demethylase, NADP-NT reductase, glucose-6-phosphatase, or lipid conjugated diene concentration) when measured 2 hours after compound administration (Reynolds 1972). Each of these parameters is an indicator of microsomal function. The authors postulated that the observed lack of effects could have been the result of slow uptake of hexachloroethane by the liver in a 2-hour period. Gastrointestinal absorption of hexachloroethane in mineral oil is probably minimal because, unlike olive oil, mineral oil cannot be digested. Dissolved lipophilic materials could be excreted in the feces soon after administration because mineral oil can act as a laxative. Thus, the author s hypothesis that minimal hexachloroethane would reach the liver in 2 hours is reasonable. 

Pharmacokinetics Rapidly and extensively absorbed after PO administration. Protein binding 31%. Metabolized in the liver by oxidation. Excreted in urine. Half-life 4-5.4 hr. 

It is readily absorbed from the GI tract with peak plasma concentration occurring two hours after ingestion. It is 98% bound to plasma proteins and it is extensively metabolised in the liver by oxidation and by conjugation with glucuronic acid. 

Small molecules are eliminated from the body largely by means of drug metabolism enzymes in the liver and other tissues and by urinary excretion. Large molecules are also eliminated by renal and hepatic mechanisms. Proteins that are less than 40 to 50 kDa are cleared by renal filtration with little or no tubular reabsorption. Larger proteins are less likely to be filtered but may be subject to phagocytosis in hepa-tocytes and Kupfer cells in the liver. Protein biotransformation—denaturation, proteolysis, and oxidative metabolism—is also important. 

The peak plasma concentration is reached 2 h after oral administration. The degree of binding of phenylbutazone to plasma proteins is 98%. The long elimination half-life of phenylbutazone (mean -70 h) exhibits large interindividual and intraindividual variation. It is metabolized in the liver by oxidation and glucuronidation and excreted in the urine and to a lower degree (-25%) in the faeces (Aarbakke, 1978). Oxyphenbutazone is an active metabolite of phenylbutazone. The metabolic pathway of phenylbutazone is shown in Scheme 72. 

Not all data confirm accumulation of protein oxidation products with age. For example, comparison of 9-month-old and 24-month-old female Long-Evans/Wistar hybrid rats did not demonstrate any age-related increase of o-tyrosine and 3-nitrotyrosine in the heart, skeletal muscle, and liver. These observations were interpreted as indications suggesting that proteins damaged by the hydroxyl radical and reactive nitrogen species did not accumulate in these tissues with advancing age (L7). Dityrosine could not be detected in human plasma proteins or haemoglobin (with the detection limit of 1 pmol/mg protein) (D3), but may accumulate in... 

Quinine is rapidly absorbed orally. It is metabolized in the liver by oxidation to several polar hydroxy metabolites. The volume of distribution is 1 or 21 kg and protein binding is 70%, although plasma binding of 90% or more has been reported in malaria patients. Quinine is excreted by the kidneys 10% is excreted as unchanged drug. The therapeutic half-life of quinine is 11.1+ 4.1 h, and may be longer in malaria patients due to hepatic impairment. The half-life can more than double at toxic doses to 26.5 +5.8 h. 

During the first step, a one-electron oxidation yields a phenoxy radical (Ar-0 ). The presence of the radical was supported by fast flow ESR spectroscopy in the presence of horseradish peroxidase. In the second one-electron oxidation, the phenoxy radical is oxidized to NAPQl. As described in Figure 33.21, the highly electrophilic NAPQl may easily react with glutathione or protein thiol groups according to a Michael-type addition. The attack of liver protein thiol... 

Chemical transformations in the liver are greatly facilitated by the action of enzymes within the smooth endoplasmic reticulum of hepatocytes (often called the microsomal fraction). Phase I reactions (oxidation, reduction, and hydrolysis reactions) convert molecules into more polar forms that usually differ in biological activity from the parent form. Oxidation reactions occur primarily under the direction of a family of enzymes called P450- Non-specific esterases in the liver, plasma, and other sites catalyze the hydrolysis of esters, whereas amides are hydrolyzed in the liver. Protein drugs are often degraded by proteases and peptidases, which are abundant in many tissues, including the intestinal tract and plasma. Phase II reactions are conjugation reactions. 

Aromatic chemicals are metabolized into unstable arene-oxides, which, as epoxides, are comparable to potentially equivalent electrophilic carbocations. These metabolites react easily with thiol groups derived from proteins, leading, for example, to hepatotoxicity. Bromobenzene (Fig. 32.10) is oxidized into a 3-4 epoxide, which does not exhibit mutagenic or carcinogenic activity, but reacts nonenzymatically with liver proteins and produces hepatic necrosis. A secondary P450-catalysed oxidation to hydroquinone... 

Bambal RB, Hanzlik RP (1995) Brranobenzene 3, 4-oxide alkylates histidine and lysine side chains of rat liver proteins in vivo. Chem Res Toxicol 8 729-735 Benson JR, Pitsinis V (2003) Update on clinical role of tamoxifen. Curr Opin Obstet Gynecol 15 13-23... 

Kamat, J.P., Sarma, H.D., Devasagayam, T.P.A., Nesaretnam, K., and Basiron, Y., Tocotrienols from pahn oil as effective inhibitors of protein oxidation and lipid peroxidation in rat liver microsomes, ALo/. Cell. Biochem., 170, 131-138, 1998. 

In studies on the role of the adrenal hormones in amino acid metabolism, cortisone has been reported to inhibit the incorporation of glycine and alanine into liver proteins and to increase the catabolism of glycine (Clark, 1950 Sinex, 1951 Barton, 1951). Proline oxidation by kidney homogenates was depressed by adrenalectomy and restored to normal by cortisone (Umbreit and Tonhazy, 1951a, 1951b). 

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