Tolerance metabolism

Since TP, SU and IM are slow to bring about plant death, there are significant opportunities to exploit metabolism of the herbicide to influence crop tolerance. Metabolism has indeed been the overriding parameter determining crop selectivity (5c.16.17). ALS inhibiting herbicides in development and/or full commercialization are known to have selectivities to all the major crops including corn, soybeans, wheat, barley, rice, cotton and canola. 

Pharmacokinetic (dispositional or Pharmacodynamic Learned tolerance Behavioral Conditioned Acute tolerance Reverse tolerance (sensitization) Cross-tolerance metabolic)... 

ADVERSE EFFECTS OF ACE INHIBITORS Serious untoward reactions to ACE inhibitors are rare, and they generally are well tolerated. Metabolic side effects are not encountered during long-term therapy with ACE inhibitors. The drugs do not alter plasma concentrations of uric acid or Ca + and actually may improve insulin sensitivity in patients with insulin resistance and decrease cholesterol and lipoprotein(a) levels in proteinuric renal disease. 

Tolerance/Dependence Tolerance, metabolic dependence, and psychologic dependence are likely. Dependence presents much like chronic alcoholism. Upon withdrawal, convulsions, hyperthermia, and delerium may be severe enough to cause death. Tolerance/Dependence High dose, chronic therapy may lead to dependence. Abrupt withdrawal may cause syndrome that mimics alcohol withdrawal (convulsions, hyperthermia, delerium). Cross tolerance and dependence occur. 

Inoue I, Shinoda Y, Nakano T et al. Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance. Metabolism 2006 55(7) 946-952. 

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

Anesthesia. Materials that have unquestionable anesthetic properties are chloral hydrate [302-17-0] paraldehyde, dimethoxymethane [109-87-5] and acetaldehyde diethyl acetal. In iadustrial exposures, however, any action as an anesthesia is overshadowed by effects as a primary irritant, which prevent voluntary inhalation of any significant quantities. The small quantities which can be tolerated by inhalation are usually metabolized so rapidly that no anesthetic symptoms occur. 

Lactulose. 4-O-P -D-Galactopyranosyl-4-D-fmctofuranose [4618-18-2] (Chronolac) (12) may be made from lactose using the method described in Reference 9. It is a synthetic disaccharide that is not hydroly2ed by gastrointestinal enzymes in the small intestine, but is metabolized by colonic bacteria to short-chain organic acids. The increased osmotic pressure of these nonabsorbable organic acids results in an accumulation of fluid in the colon. Lactulose may not be tolerated by patients because of an extremely sweet taste. It frequently produces flatulence and intestinal cramps. 

Yeast (qv) metabolize maltose and glucose sugars via the Embden-Meyerhof pathway to pymvate, and via acetaldehyde to ethanol. AH distiUers yeast strains can be expected to produce 6% (v/v) ethanol from a mash containing 11% (w/v) starch. Ethanol concentration up to 18% can be tolerated by some yeasts. Secondary products (congeners) arise during fermentation and are retained in the distiUation of whiskey. These include aldehydes, esters, and higher alcohols (fusel oHs). NaturaHy occurring lactic acid bacteria may simultaneously ferment within the mash and contribute to the whiskey flavor profile. 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Furthermore, the GPO procedure can also be used for a preparative synthesis of the corresponding phosphorothioate (37), phosphoramidate (38), and methylene phosphonate (39) analogs of (25) (Figure 10.20) from suitable diol precursors [106] to be used as aldolase substrates [102]. In fact, such isosteric replacements of the phosphate ester oxygen were found to be tolerable by a number of class I and class II aldolases, and only some specific enzymes failed to accept the less polar phosphonate (39) [107]. Thus, sugar phosphonates (e.g. (71)/(72)) that mimic metabolic intermediates but are hydrolytically stable to phosphatase degradation can be rapidly synthesized (Figure 10.28). 

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

Desiccation tolerant species may exhibit little or no metabolic activity depending upon the extent of dehydration. In this anhydrobiotic or ametabolic state we are concerned not with metabolic perturbation but with the stability of organelles, membranes and macromolecules in a dehydrated state. However, in the initial period of rehydration, the passage to a metabolically active state poses particular problems if metabolic mayhem is to be avoided. 

Senaratna, T. McKenzie, B.D. (1986). Loss of desiccation tolerance during seed germination A free radical mechanism of injury. In Membranes, Metabolism and Dry Organisms, ed. A.C. Leopold, pp. 85-101. Ithaca, N.Y. Comstock Publishing Associates. 

Cells exposed to excessive levels of salinity have to acquire essential nutrients from a milieu with a preponderance of ions that are potentially toxic and non-essential. In this ionic environment the success of a plant cell will require intracellular tolerance and/or specific acquisition of nutrients essential for normal metabolic functioning. The cell is also exposed to an unfavourable water balance with an absolute requirement to maintain an internal osmotic regulation that favours uptake of water into the cell (Stavarek Rains, 1984 ). 

One of the metabolic responses of plants exposed to environmental stress is the production of proteins which may be qualitatively and/or quantitatively different from those produced in the absence of the stress (see Chapter 9 for general discussion). In some cases these responses have been found to depend on genotype for example, when a salt-tolerant cultivar and a salt-sensitive cultivar of barley were exposed to salt stress the shoot tissue responded by synthesising proteins which were cultivar specific. Five new proteins not found in the salt-sensitive barley were identified in the salt-tolerant cultivar (Ramagopal, 1987). No differences in proteins were found in the roots of either cultivar. 

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