Oxidative metabolites catabolism

Unlike the other fat-soluble vitamins, there is litde or no storage of vitamin D in the liver, except in oily fish. In human liver, concentrations of vitamin D do not exceed about 25 nmol per kg. Significant amounts may be present in adipose tissue, but this is not really storage of the vitamin, because it is released into the circulation as adipose tissue is catabolized, rather than in response to demand for the vitamin. The main storage of the vitamin seems to be as plasma calcidiol, which has a half-life of the order of 3 weeks (Holick, 1990). In temperate climates, there is a considerable seasonal variation, with plasma concentrations at the end of winter as low as half those seen at the end of summer (see Table 3.2). The major route of vitamin D excretion is in the bile, with less than 5% as a variety of water-soluble conjugates in urine. Calcitroic acid (see Figure 3.3) is the major product of calcitriol metabolism but, in addition, there are a number of other hydroxylated and oxidized metabolites. 

During catabolic and anabolic processes, a renovation of the molecular cellular components takes place. It should be emphasized that the catabolic and anabolic pathways are independent of each other. Be these pathways coincident and differing in the cycle direction only, the metabolism would have been side-tracked to the so-called useless, or futile, cycles. Such cycles arise in pathology, where a useless turnover of metabolites may occur. To avoid this undesirable contingency, the synthetic and degradative routes in the cell are most commonly separated in space. For example, the oxidation of fatty acids occurs in the mitochondria, while the synthesis thereof proceeds extramitochondrially, in the microsomes. 

Wilson and Madsen [152] used the metabolic pathway for bacterial naphthalene oxidation as a guide for selecting l,2-dihydroxy-l,2-dihydronaphthalene as a unique transient intermediary metabolite whose presence in samples from a contaminated field site would indicate active in situ naphthalene biodegradation (Fig. 26). Naphthalene is a component of a variety of pollutant mixtures. It is the major constituent of coal tar [345], the pure compound was commonly used as a moth repellant and insecticide [345], and it is a predominant constituent of the fraction of crude oil used to produce diesel and jet fuels [346]. Prior studies at a coal tar-contaminated field site have focused upon contaminant transport [10,347], the presence of naphthalene catabolic genes [348, 349], and non-metabolite-based in situ contaminant biodegradation [343]. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

As a catabolic pathway, it initiates the terminal oxidation of energy substrates. Many catabolic pathways lead to intermediates of the tricarboxylic acid cycle, or supply metabolites such as pyruvate and acetyl-CoA that can enter the cycle, where their C atoms are oxidized to CO2. The reducing equivalents (see p. 14) obtained in this way are then used for oxidative phosphorylation—I e., to aerobically synthesize ATP (see p. 122). 

Figure 2 Summary of the major oxidative routes for IAA catabolism. These include oxidation at the 2-position to form oxIAA and its metabolites (A and D), the recently described oxidations at indole-6 (B) and the formation of N-glucosides (C), and, finally, the conjugation to lAA-aspartate and its subsequent oxidation (E).

An alternative approach to determining requirements is to measure the fractional rate of catabolism of the vitamin by use of a radioactive tracer, then determine the intake that would be required to maintain an appropriate level of liver reserves. As discussed in Section2.2.1.1, when the liver concentration rises above 70 /rmol per kg, there is increased activity of the microsomal oxidation of vitamin A and biliary excretion of retinol metabolites. The fractional catabolic rate is 0.5% per day assuming 50% efficiency of storage of dietary retinol, this gives a mean requirement of 6.7 /rg per kg of body weight and a reference intake of 650 to 700 /rg for adult men (Olson, 1987a). Reference intakes for vitamin A are shown in Table 2.4. 

The first metabolite 8 -HOABA (24) in the oxidative catabolism of ABA is extremely difficult to isolate without 8 -C>-protection because it... 

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