Cytochrome kidney

Hydroxy vitamin D pools ia the blood and is transported on DBF to the kidney, where further hydroxylation takes place at C-1 or C-24 ia response to calcium levels. l-Hydroxylation occurs primarily ia the kidney mitochondria and is cataly2ed by a mixed-function monooxygenase with a specific cytochrome P-450 (52,179,180). 1 a- and 24-Hydroxylation of 25-hydroxycholecalciferol has also been shown to take place ia the placenta of pregnant mammals and ia bone cells, as well as ia the epidermis. Low phosphate levels also stimulate 1,25-dihydtoxycholecalciferol production, which ia turn stimulates intestinal calcium as well as phosphoms absorption. It also mobilizes these minerals from bone and decreases their kidney excretion. Together with PTH, calcitriol also stimulates renal reabsorption of the calcium and phosphoms by the proximal tubules (51,141,181—183). 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Lecoeur, S., Andre, C., and Beaune, P.H., Tienilic acid-induced autoimmune hepatitis Antiliver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9, Mol. Pharmacol., 50,326, 1996. 

No information is available on the adverse health effects of hexachloroethane in humans. Animal studies revealed that hexachloroethane primarily causes liver and kidney toxicity. Effects on the nervous system and lungs have also been reported. The mechanism by which these effects are mediated is not well characterized. Reductive metabolism by cytochrome P-450 and production of a free radical intermediate have been suggested as factors in hexachloroethane-induced hepatotoxicity (Nastainczyk et al. 1982a Thompson et al. 1984 Town and Leibman 1984). Accordingly, one possible approach may be to reduce free radical injury. To that end, oral administration of N-acetylcysteine can be used as a means of reducing free radical injury. Also, oral administration of vitamin E and vitamin C may be of value since they are free radical scavengers. 

Servent and colleagues [52] reported that GTN is metabolised in rat liver microsomes by an NADPH-dependent cytochrome P-450 system, yielding GDN, glyceryl mononitrate (GMN) and NO. Moreover, Schroeder and Schroer [53] showed that inhibitors of cytochrome P-450 reduce cGMP stimulation by GTN in kidney epithelial cells. 

Inhibitors of cytochrome P-450 reduce cyclic GMP stimulation by glyceryl trinitrate in LLC-PKi kidney epithelial cells. Naunyn Schmiedebergs Arch. Pharmacol. 342 (1990), p. 616-618... 

Sawamura A, Kusunose E, Satouchi K, et al. Catalytic properties of rabbit kidney fatty acid omega-hydroxylase cytochrome P-450ka2 (CYP4A7). Biochim Biophys Acta 1993 1168(1 ) 30-36. 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

Cytochrome P4502E1, also microsomally located, catalyzes the hydroxylation of phenol to form hydroquinone (and to a much lesser extent catechol), which is then acted upon by the phase II enzymes (Benet et al. 1995 Campbell et al. 1987 Gut et al. 1996 McFadden et al. 1996). All three enzyme systems are found in multiple tissues and there is competition among them not only for phenol but for subsequent oxidative products, like hydroquinone. As a consequence, the relative amount of the products formed can vary based on species, dose and route of administration. In vivo, the gastrointestinal tract, liver, lung, and kidney appear to be the major sites of phenol sulfate and glucuronide conjugation of simple phenols (Cassidy and Houston 1984 Powell et al. 1974 Quebbemann and Anders 1973 ... 

In vitro assays are increasingly being used. Some of the reasons are cost, availability of more rapid results, and avoidance of negative publicity. Assays such as cytochrome P-450 enzymes, the Ames test, and the mouse lymphoma tk test are in vitro methods. For absorption studies, Caco-2 (Exhibit 5.9) and Madin-Darby canine kidney cell assays are now routinely used. Hepatocyte cell lines with metabolism capacity are being developed to test drug metabolism and toxicity. All these examples show that, where possible, pharmaceutical firms are gradually dispensing with animal studies. 

Meyer RP, Podvinec M, Meyer UA. 2002. Cytochrome P450 CYPlAl accumulates in the cytosol of kidney and brain and is activated by heme. Mol Pharmacol 62 1061-1067. 

Metabolic pathways of chloroform biotransformation are shown in Figure 2-3. Metabolism studies indicated that chloroform was, in part, exhaled from the lungs or was converted by oxidative dehydrochlorination of its carbon-hydrogen bond to form phosgene (Pohl et al. 1981 Stevens and Anders 1981). This reaction was mediated by cytochrome P-450 and was observed in the liver and kidneys (Ade et al. 1994 Branchfiower et al. 1984 Smith et al. 1984). In renal cortex microsomes of... 

It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes. 

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