Cytochrome hepatic microsomal, effects

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Ebel RE. 1980. In vitro effects of chlordecone (Kepone) on hepatic microsomal cytochrome P-450. Pesticide Biochemistry and Physiology 14(3) 221-226. 

Gigon PL, Gram TE, Gillette JR. 1969. Studies on the rate of reduction of hepatic microsomal cytochrome P-450 by reduced nicotinamide adenine dinucleotide phosphate Effect of drug substrates. Mol Pharmacol 5 109-122. 

Mueller and Miller (33) and Brodie et al. (34) were the first to show that enzymes in the microsomal fraction of rat liver could effectively oxidize xenobiotics. Comparable enzymes (aryl hydrocarbon monooxygenases) were later reported in the hepatic tissues of fresh water and marine fish by Creaven et al. (35) and Buhler and Rasmusson (36). Reconstituted hepatic microsomal systems require cytochrome P-450 for monooxygenase activity in both mammals (37) and fish (38,39). Bend et al. 

An obvious difference was also noted between control and induced skate hepaticdnicrosomal AHH activity in the presence of a-naphthoflavone (10 M). This compound, when added in vitro at this or higher concentrations, caused significant stimulation of AHH activity in control animals (about 3-fold) but inhibition (80%) was found in DBA-pretreated skates. Similar results were earlier reported for control and 3-methylcholanthrene-treated rats (23), where it appears that the response is due to differential effects of a-naphthoflavone on hepatic microsomal cytochrome P-450 (stimulated) and cytochrome P-448 (inhibited) (24). Our data suggests that there may be a novel form of cytochrome P-450 synthesized in skate liver in response to polycyclic hydrocarbon administration, even though there was no hypsochromic shift in the carbon monoxide difference spectrum of dithionite reduced hepatic microsomes from DBA-treated skates (relative to hepatic microsomes from control fish). 

Dichlorobenzidine is an effective inducer of its own metabolic activation (Iba 1987a). The enhancement of 3,3 -dichlorobenzidine mutagenesis has been associated with the induction of cytochrome P-450d (Iba and Thomas 1988), and may result in the elevation of its carcinogenicity. In other animal studies, 3,3 -dichlorobenzidine was also shown to be a potent inducer of hepatic microsomal enzymic activities mediated by cytochrome-P-448 and P-450 (Iba and Sikka 1983 Iba and Thomas 1988). Consequently, it has been suggested that the hepatocarcinogenicity of 3,3 -dichlorobenzidine may be due, at least in part, to the induction of hepatic cytochrome P-488 and DNA-adduction. 

Most cases of intoxication from industrial exposure have been mild, with rapid onset of eye irritation, headache, sneezing, and nausea weakness, light-headedness, and vomiting may also occur. Acute exposure to high concentrations may produce profound weakness, asphyxia, and death. Acrylonitrile is metabolized to cyanide by hepatic microsomal reactions. Deaths from acute poisoning result from inhibition of mitochondrial cytochrome oxidase activity by metabolically liberated cyanide. Inhalation of more moderate concentrations for a longer period of time leads to damage to the liver tissues in addition to central nervous system (CNS) effects. ... 

Hexanone has also been shown to potentiate the neurotoxic effects of some compounds. In hens, dermal or inhalation exposure to 2-hexanone in combination with dermal application of the pesticide O-ethyl-O-4-nitrophenyl phenylphosphonothioate (EPN) has resulted in earlier onset and far more severe clinical and histological manifestations of neurotoxic effects than with either chemical exposure alone (Abou-Donia et al. 1985a, 1985b). The authors speculated that this potentiation effect may have been due to induction of hepatic microsomal cytochrome P-450 by EPN, leading to increased metabolism of 2-hexanone to its neurotoxic metabolite, 2,5-hexanedione. An alternate explanation is that local trauma to the nervous tissue produced by 2-hexanone and EPN might increase vascular permeability and thus increase the entry of these compounds and their metabolites from circulation. 

Murray M, Farrell GC. 1984. Different effects of carbon tetrachloride toxicity and cirrhosis on substrate binding to rat hepatic microsomal cytochrome P-450. Biochem Pharmacol 33 687-9. 

Evans, J.G, Appleby, E.C., Lake, B.G Coiming, D M. (1989) Studies on the induction of cholangiofibrosis by coumarin in the rat. Toxicology, 55, 207-224 Faurschou, P. (1982) Toxic hepatitis due to benzo-pyrone. Hum. Toxicol, 1, 149-150 Fentem, J.H. Fry, J.R. (1991) Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities. Xenobiotica, 21, 895-904... 

Wade, A.E., Evans, J.S., Stemson, L.A. Gammans, R.E. (1977) Interaction of nitromethane with reduced hepatic microsomal cytochrome P 450. Biochem. Pharmacol., 26, 963-967 Zitting, A., Nickels, J. Savolainen, H. (1982) Comparison of acute toxic effects of intia-peritoneally injected nitromethane and nitroethane in rats. Toxicol. Lett., 13, 189-194... 

Zang et al [140] reported the liver protective effects of the saponins isolated from A. membranaceus and A. sieversianus against chemical injury induced by CCU, D-galactosamine and acetaminophen in mice. In all cases there were positive activities and the saponins inhibited the rise in SGPT levels, decreased the malondialdehyde (MDA) content and increased the glutathione reduced (GSH) concentration in mouse liver. The same compounds were also evaluated in cultured rat hepatocytes, and the results indicated that the activity may be due to to the antioxidative activity of the saponins, since the content of liver protein in treated mice was more than the control. Moreover, in all treated mice, the level of hepatic microsomal cytochrome P-450 was increased. The liver metabolism and immunoregulating action produced by saponins may be also involved in their hepato-protective effects. Similar results were obtained by Zhang et al [141] when they studied the activity in vitro and... 

Assessment of the potential impact of hepatic dysfunction on the pharmacokinetic and adverse event profiles of donepezil is of primary importance, as donepezil is orally administered and subject to extensive first-pass metabolism. In addition, both preclinical and clinical studies have demonstrated that donepezil is metabolized primarily in the liver [8-11]. In vitro studies using human hepatic microsomes have shown that the cytochrome P-450 isoenzyme (CYP-3A4) is mostly responsible for the metabolism of donepezil, with CYP-2D6 playing a minor role. With this in mind, this study was designed to assess the effects of compromised hepatic function on the pharmacokinetics of donepezil HC1 [8-11]. 

Table III. Effects of Dietary Fat and Antioxidants on Hepatic Microsomal Cytochrome Plt5Q Levels in Female Sprague-Dawley Rats...

Lake BG, Tredger JM, Gray TJ, et al. 1984c. The effect of peroxisome proliferators on the metabolism and spectral interaction of endogenous substrates of cytochrome P-450 in rat hepatic microsomes. Life Sci 35 2621-2626. 

Characterization of 1,1-dichloroethane s metabolism relies heavily on in vitro data. These studies reveal that the biotransformation process is mediated by cytochrome P-450 with hepatic microsomes being the most effective. Identification of products in these microsomal studies allows for the prediction of metabolic pathways. However, exposure to 1,1-dichloroethane under in vivo conditions may alter substrate availability and consequently alter the metabolic scheme. In vivo studies would provide a better understanding of the rate and extent of 1,1- dichloroethane metabolism and a more realistic perspective of its metabolic fate. This information would allow more accurate prediction of the potential of 1,1-dichloroethane to induce toxic effects, and aid in devising methods to detoxify exposed persons. 

In hepatic microsomes, omeprazole inhibited cytochrome P450-mediated metabolic reactions in vitro. This effect was comparable to the inhibition caused by cimetidine with respect to the extent of the inhibitory effect and the effective concentrations [110]. Under well-defined clinical conditions, an... 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

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