Metabolic conversions

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

The overall reaction for the metabolic conversion of glucose to dtric add is glucose + 0.5 O2 - dtric add + 2H2O... 

C14-0128. What is the efficiency of the metabolic conversion of palmitic acid to ATP Compute the number of grams of palmitic acid that would have to be metabolized to provide the heat to warm a swimmer from whose skin 75 g of water evaporates. 

While the ddNs and ANPs must be converted intracellularly to their 5 -triphosphates (ddNTPs) or diphosphate derivatives before they can interact as competitive inhibitors/alternate substrates with regard to the natural substrates (dNTPs), the NNRTIs do not need any metabolic conversion to interact, noncompetitively with respect to the dNTPs, at an allosteric, non-substrate binding site of the HIV-1 RT. Through the analysis of NNRTI-resistant mutants, combined with site-directed mutagenesis studies, it has become increasingly clear which amino acid residues are involved in the interaction of the NNRTIs with HIV-1 RT, and, since the conformation of the HIV-1 RT has been resolved at 3.0 A resolution [73], it is now possible to visualize the binding site of the NNRTIs [74],... 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

PAH radical cations are also involved in the metabolic conversion of PAH to PAH diones. Carcinogenicity studies of PAH in rat mammary gland indicate that only PAH with ionization potential low enough for activation by one-electron oxidation induce tumors in this target organ. These results and others indicate that one-electron oxidation of PAH is involved in their tumor initiation process. 

The products formed during lipid peroxidation include unsaturated aldehydes, such as 4-hydroxynonenal. Their quantification is of great interest because of their extremely reactive and cytotoxic properties. This extreme reactivity and metabolic conversion, however, may make them unsuitable as test analytes for in vivo antioxidant activity studies except at high levels of oxidative stress. Furthermore, simple chemical tests such as the TBARS (thiobarbituric acid reactive substances) and LPO-586 (colorimetric... 

Bioconcentration factors of dioxins in fishes are relatively low compared to other chlorinated aromatic compounds because of the low metabolic conversion of dioxins, their low available concentrations in test systems, and their highly variable uptake rates (de Voogt et al. 1990). In general, bioconcentration factors for persistent superlipophilic chemicals, such as OCDD, derived for freshwater fishes from supersaturated solutions may seriously underestimate the true BCF (Geyer... 

Fung and colleagues examined the metabolic conversion of organic nitrates in sub-cellular fractions of bovine coronary artery smooth muscle cells [66, 67]. They found NO-generating capacity to be present in membrane fractions and, with the use of marker enzymes, identified plasma membrane as the primary location. The enzyme involved in bioconversion was not glutathione-S-transferase [68] and differed from those that catalyse activation of organic nitrites [69]. Partial purification [70] established that the molecular sizes of the native enzyme and subunits were approximately 200 kDa and 58 kDa respectively, and that enzymic activity depends on the presence of a free thiol group. 

Formation of. glucuronide conjugates is a major metabolic conversion for many lipid-soluble compounds. The product glucuronides are more water soluble and usually more readily excreted. The glucuronic acid donor in this reaction is... 

FIGURE 1.1 Metabolic conversion of prodrugs to pharmacologically active agents. 

Metabolism is the process by which chemicals are changed by the body. In fact, very few foreign chemicals that enter the body are excreted unchanged. Most are chemically modified. In general, metabolism results in chemicals that are more polar and water soluble, and more easily excreted. Examples of the more common metabolic conversions are shown in Table 18.5. In general, the vast majority of... 

The processes of metabolic conversion are frequently involved in the mechanisms of toxicity and carcinogenicity. 

The nervous system is the most sensitive target for cyanide toxicity, partly because of its high metabolic demands. High doses of cyanide can result in death via central nervous system effects, which can cause respiratory arrest. In humans, chronic low-level cyanide exposure through cassava consumption (and possibly through tobacco smoke inhalation) has been associated with tropical neuropathy, tobacco amblyopia, and Leber s hereditary optic atrophy. It has been suggested that defects in the metabolic conversion of cyanide to thiocyanate, as well as nutritional deficiencies of protein and vitamin B12 and other vitamins and minerals may play a role in the development of these disorders (Wilson 1965). 

Kunz DA, Nagappan O, Silva-Avalos J, et al. 1992. Utilization of cyanide as a nitrogenous substrate by Pseudomonas fluorescens NCIMB 11764 Evidence for multiple pathways of metabolic conversion. Appl Environ Microbiol 58(6) 2022-2029. 

Although all quinones have the same functional group, their physicochemical behavior and mechanisms of toxicity vary due to the presence of different substituents. Thus, the cellular aspects of quinone metabolism are diverse, and a single mechanism explaining these actions has not yet been identified. Furthermore, it is noteworthy that the cytotoxicity of some xenobiotic compomids, such as benzene, benzo[a]pyrene, and 1-naphthol, may partly be caused by metabolic conversion of these compoimds to quinones (Snyder et al, 1987 Zheng et al, 1997). 

No studies were located regarding metabolism of heptachlor or heptachlor epoxide in humans. However, animal studies have shown that heptachlor undergoes epoxidation to produce heptachlor epoxide, which is more toxic than its parent compound. Heptachlor epoxide is further metabolized and excreted. In an in vitro liver study, human and rat liver microsomes metabolized heptachlor to the same products but in different proportions (Tashiro and Matsumura 1978). It was also shown in this study that rat microsomal preparations were four times more efficient in the metabolic conversion of heptachlor to heptachlor epoxide than were human microsomal preparations. 

Ibuprofen is an interesting case, in that the (5)-(+)-form is an active analgesic, but the ( )-(—)-enantiomer is inactive. However, in the body there is some metabolic conversion of the inactive (I )-isomer into the active (5 )-isomer, so that the potential activity from the racemate is considerably more than 50%. Box 10.11 shows a mechanism to account for this isomerism. 

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