Metabohc pathways

Cleavage of C-17 JilkylSubstituents. Resulting primarily in cholan-17-ones, this is a relatively minor metabohc pathway. Corticosterone is not known to... 

Biorational approaches have proven useful in the development of classes of herbicides which inhibit essential metaboHc pathways common to all plants and thus are specific to plants and have low toxicity to mammalian species. Biorational herbicide development remains a high risk endeavor since promising high activities observed in the laboratory may be nullified by factors such as limitations in plant uptake and translocation, and the instabiHty or inactivity of biochemical en2yme inhibitors under the harsher environmental conditions in the field. Despite these recogni2ed drawbacks, biorational design of herbicides has shown sufficient potential to make the study of herbicide modes of action an important and growing research area. 

Biochemical oxidation of lactate to pymvate by lactate dehydrogenase is a well-known enzymatic reaction ia metaboHc pathways. 

Oxidative Reactions. The majority of pesticides, or pesticide products, are susceptible to some form of attack by oxidative enzymes. For more persistent pesticides, oxidation is frequently the primary mode of metaboHsm, although there are important exceptions, eg, DDT. For less persistent pesticides, oxidation may play a relatively minor role, or be the first reaction ia a metaboHc pathway. Oxidation generally results ia degradation of the parent molecule. However, attack by certain oxidative enzymes (phenol oxidases) can result ia the condensation or polymerization of the parent molecules this phenomenon is referred to as oxidative coupling (16). Examples of some important oxidative reactions are ether cleavage, alkyl-hydroxylation, aryl-hydroxylation, AJ-dealkylation, and sulfoxidation. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Methods for the preparation of L-ascorbic acids having isotopic C, H, O in various positions have been described and reviewed (104,105). Labeled L-ascorbic acid has played an important role in the elucidation of the metaboHc pathway of L-ascorbic acid in plants and animals. 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

Microorganisms exhibit nutritional preferences. The enzymes for common substrates such as glucose are usually constitutive, as are the enzymes for common or essential metabohc pathways. Furthermore, the synthesis of enzymes for attack on less common substrates such as lactose is repressed by the presence of appreciable amounts of common substrates or metabolites. This is logical for cells to consei ve their resources for enzyme synthesis as long as their usual substrates are readily available. If presented with mixed substrates, those that are in the main metabolic pathways are consumed first, while the other substrates are consumed later after the common substrates are depleted. This results in diauxic behavior. A diauxic growth cui ve exhibits an intermediate growth plateau while the enzymes needed for the uncommon substrates are synthesized (see Fig. 24-2). There may also be preferences for the less common substrates such that a mixture shows a sequence of each being exhausted before the start of metabolism of the next. 

Compartmentation of pathways in separate subcellular compartments or organelles permits integration and regulation of metabolism. Not all pathways are of equal importance in all cells. Figure 15-7 depicts the subceh lular compartmentation of metabohc pathways in a hepatic parenchymal cell. 

A.G. Hackett, Chloroacetanilides in Metabohc Pathways of Agrochemicals Part 1 Herbicides and Plant Growth Regulators, ed. T. Roberts, Royal Society of Chemistry, Cambridge, pp. 179-218(1998). 

Francis, J.C. and Hansche, PE. (1972) Directed evolution of metabohc pathways in microbial populations. I. Modification of the acid phosphatase pH optimum in S. cerevisiae. Genetics, 70, 59—73. 

Animal tests will, in general, be needed for the clarification of positive findings in in vitro tests and in case of specific metabohc pathways that cannot be simulated adequately in vitro. 

Chaturvedi et al. (1991) studied the effects of mixtures of parathion, toxaphene, and/or 2,4-D on the hepatic mixed-function oxygenase in ICR male mice. They found that a 7-day toxaphene pretreatment enhanced the hepatic biotransformation of parathion and its metabohte paraoxon, both in the presence and absence of NADP. However, in the absence of NADP the enhancement was minor. The authors suggested that toxaphene induced the metabohc pathways of parathion and paraoxon involving the mixed-function oxygenase and that paraoxonase is not involved in the... 

A second dietary trace element, selenium, is also essential for normal thyroid hormone metabohsm. Selenium in the form of selenocysteine is a required component for three enzymes that remove iodide from thyroid hormones. Deiodination is the major metabohc pathway by which T4 and T3 are cleared from the system. After secretion by the thyroid gland, T4 may be deiodinated to yield either T3 or the physiologically inactive reverse Tj (3,3, 5 -triiodothyronine, or rX3). T3 and rTj are further deiodinated to form less active metabolites. Selenium, like iodine, is deficient in many areas of the world. 

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