Vitamin Microsomes

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

The anticoagulant rodenticides warfarin and superwarfarins are toxic because they have high affinity for a vitamin K binding site of hepatic microsomes (Chapter 11, Section 11.2.4). In theory, an ideal biomarker would... 

Battioni, )., Fontecave, M., Jaouen, M. and Mansuy, D. (1991). Vitamin E derivatives as new potent inhibitors of microsomal lipid peroxidation. Biochem. Biophys. Res. Commun. 174, 1103-1108. 

This mechanism is now considered to be of importance for the protection of LDL against oxidation stress, Chapter 25.) The antioxidant effect of ubiquinones on lipid peroxidation was first shown in 1980 [237]. In 1987 Solaini et al. [238] showed that the depletion of beef heart mitochondria from ubiquinone enhanced the iron adriamycin-initiated lipid peroxidation whereas the reincorporation of ubiquinone in mitochondria depressed lipid peroxidation. It was concluded that ubiquinone is able to protect mitochondria against the prooxidant effect of adriamycin. Inhibition of in vitro and in vivo liposomal, microsomal, and mitochondrial lipid peroxidation has also been shown in studies by Beyer [239] and Frei et al. [240]. Later on, it was suggested that ubihydroquinones inhibit lipid peroxidation only in cooperation with vitamin E [241]. However, simultaneous presence of ubihydroquinone and vitamin E apparently is not always necessary [242], although the synergistic interaction of these antioxidants may take place (see below). It has been shown that the enzymatic reduction of ubiquinones to ubihydroquinones is catalyzed by NADH-dependent plasma membrane reductase and NADPH-dependent cytosolic ubiquinone reductase [243,244]. 

In the case of ubiquinones we have already considered the ability of quinones to react with superoxide and other free radicals. Naphthoquinones, vitamin K and its derivatives, especially menadione, are the well known producers of superoxide through redox cycling with dioxygen. However, in 1985, Canfield et al. [254] have shown that vitamin K quinone reduced the oxidation of linoleic acid while vitamin K hydroquinone stimulated lipid peroxidation. Surprisingly, later on, conflicting results were reported by Vervoort et al. [255] who found that only hydroquinones of vitamin K and its analogs inhibited microsomal lipid peroxidation. 

T. M. Guenthner, D. Cai, R. Wallin, Co-Purification of Microsomal Epoxide Hydrolase with the Warfarin-Sensitive Vitamin Kx Oxide Reductase of the Vitamin K Cycle , Biochem. Pharmacol. 1998, 55, 169 - 175. 

The active forms of the D vitamins are la,25-dihydroxy-vitamin Dj and 25-hydroxy-vitamin Dj. They are formed by enzymatic hydroxylation in the liver microsomes and then in the kidney mitochondria by a ferredoxin flavoprotein and cytochrome P-450. The 1,25-dihydroxy vitamin is then transported to the bone, intestine, and other target organs (kidneys, parathyroid gland). Consequently, it can be considered a hormone since it is produced in one organ but used elsewhere. It mobilizes calcium and phosphate and also influences the absorption of these ions in the intestine, thus promoting bone mineralization. The hormone is also active in relieving hypoparathyroidism and postmenopausal osteoporosis, which, for example, results in the brittle bones of elderly women. 

CYP2E1 is the principal catalyst of vinylidene chloride metabolism and metabolic activation. This conclusion is based on the following findings. Inducers (ethanol, acetone) and inhibitors (diethyldithiocarbamate) increase and decrease, respectively, metabolic activation of vinylidene chloride in mouse liver microsomes and in isolated mouse hepatocytes (Kainz et al., 1993 Lee Forkert, 1994 Dowsley et al., 1995). Vitamin A treatment increases CYP2E1 activity in rat liver microsomes and also potentiates vinylidene chloride toxicity in liver slices from treated animals (Wijeweera et al., 1996). In mouse liver microsomes in vitro, vinylidene chloride decreases CYP2E1 levels (Lee Forkert, 1994). 

All are probably bound to the microsomal membranes.503 507a An NADPH-dependent reductase reduces vitamin K quinone to its hydroquinone form. Conversion of Glu residues to Gla residues requires this reduced vitamin K as well as 02 and C02. During the carboxy-lation reaction the reduced vitamin K is converted into vitamin K 2,3-epoxide (Eq. 15-55).508 The mechanism is uncertain but a peroxide intermediate such as that shown in Eq. 15-56 is probably involved. This could be used to generate a hydroxide ion adjacent to the pro-S -H of the glutamate side chain of the substrate. This hydrogen could be abstracted by the OH to form... 

Vitamin D3 (cholecalciferol) can be made in the skin from 7-dehydrocholesterol in the presence of ultraviolet light (see fig. 24.13). Vitamin D3 is formed by the cleavage of ring 3 of 7-dehydrocholesterol. Vitamin D3 made in skin or absorbed from the small intestine is transported to the liver and hydroxylated at C-25 by a microsomal mixed-... 

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

Table I summarizes the status of vitamin E and Se in various tissues obtained from rats subjected to altered vitamin E and/or Se nutrition. It is evident from the Table that the animals fed on vitamini E and/or Se-deficient diets showed marked decrease in tissue levels of vitamin E and/or Se respectively. This indicates that the diets employed in these experiments induced desirable deficiency states of vitamin and/or Se. In general, vitamin E levels were affected more in microsomes than in cytosols under vitamin E-deficiency states.

Table II. Microsomal Heme Peroxidase Activity in Rats Fed Diets with Altered Vitamin E and/or Selenium Nutrition for 5 Weeks...

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