Vitamins, hepatic accumulation

Critical to vitamin D3 action is its further metabolic conversion to more active compounds (Figure 1.3). Via its transport by DBP, vitamin D3 accumulates in the liver [48]. In rats, as much as 60-80% of an injected or oral dose of vitamin D3 locates to the liver [49-51], Intestinal absorption of vitamin D3 is in association with the chylomicron fraction via the lymphatic system. Vitamin D3 is delivered to the liver in blood from the thoracic duct only a few hours post ingestion [44], A specific portion of hepatic vitamin D3 in the rat is converted to 25-OH-D3 by a 25-hydroxylase system in the endoplasmic reticulum of hepatocytes [52, 53]. This enzyme (Km 10"8 M) is regulated to an extent by 25-OH-D3 and its metabolites. Higher concentrations of vitamin D3 are handled by a second 25-hydroxylase located in liver mitochondria [54], This enzyme, also known as CYP27, 27-hydroxylates cholesterol and thus appears less discriminating than the microsomal 25-OHase which does not use cholesterol as substrate [55, 56]. In humans, however,... 

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

Other notable findings concerning vitamin-E deficient animals established hepatic lesions [38-40] and accumulation of lipopigment [41], while addition of the vitamin to the diet of rabbits evoked enhanced immune function [42], These early studies in vitamin E deficiency states in animals produced sufficient diverse and interesting observations to generate much of the data currently available. 

Quiescent, perisinusoidal hepatic stellate cells (HSC) accumulate retinoids (vitamin A and its metabolites) in large cytoplasmic droplets and store about 80% of body s retinoids. However, these cells also express the muscle protein desmin and become activated to myofibroblasts upon exposure to hepatotoxicants. Activated HSC synthesize extracellular matrix proteins, especially when stimulated by cytokines and growth factors (see Section 28.4.2). 

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. 

Also see color figure.) Hepatic vitamin K metabolism. Oral anticoagulant drugs act indirectly on the process of glu carboxylation of the vitamin K dependent proteins. The vitamin K antagonists block the reduction of the reaction intermediate, vitamin K-epoxide, that results in the accumulation of vitamin K-epoxide and other nonfunctional forms of vitamin K. Without cycling of the vitamin K-related reaction intermediates in the cycle shown, a depletion of functional vitamin K occurs. Vitamin K antagonists do not block polypeptide synthesis and formation of noncarboxylated proteins occurs. These noncarboxylated proteins are still secreted from the liver and account for nearly normal levels of each of the vitamin K-dependent proteins that can be detected by immunoassay (sometimes called PIVKA, proteins induced in vitamin K absence). 

The accumulation of vitamin A in the livers of chickens and ducks diu -ing growth and development seems to follow the same pattern as that observed for several species of mammals. The average concentration (I-U./ gm) found by Harms (1942a,b) for chicks was 61 (N = 24) and for chickens 905 (V = 322), indicating 15 times higher hepatic vitamin A levels in the adult than in the young birds. A pronounced difference was similarly observed by Harms between the liver vitamin A content in ducklings (7 I.U./ gm N = 24) and ducks (247 I.U./gm N = 20). 

Lewis etal, 1981), and that remaining in the critically depleted pool is released at a reduced rate. The consequence is a relative accumulation of hepatic apo-RBP owing to the limited availability of retinol from internal and external supplies. At an intermediate level of hepatic vitamin A nutriture (Fig. 3B), a portion of newly absorbed retinol is mobilized, presumably to satisfy any peripheral tissue insufficiency that may be transiently created by fasting the remainder, however, enters the hepatic pools for short- or long-term storage (Sewell et al., 1967 Varma and Beaton, 1972 Lewis et al., 1981). It is generally believed that the hepatic pools serve to buffer dietary fluctuations in supply and to match circulating levels of RBP-retinol with rates of tissue utilization (Underwood et al., 1979). 

Lee-Chen SF, Yu CT, Jan KY (1992) Effect of arsenite on the DNA repair of UV-irradiated Chinese hamster ovary cells. Mutagenesis 7 51-55 Li Y, Togashi Y, Sato S, Emoto T, Kang J-H, Takeichi N, Kobayshi H, Kojima Y, Une Y, Uchino J (1991) Abnormal copper accumulation in non-cancerous and cancerous liver tissues of LEC rats developing hereditary hepatitis and spontaneous hepatoma. Jpn J Cancer Res 82 490-492 Lin XH, Sugiyama M, Costa M (1991) Differences in the effect of vitamin E on nickel sulfide or nickel chloride-induced chromosomal aberrations in mammalian cells. Mutat Res 260 159-164... 

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