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To lengthen its half-life and duration of action managing diabetes 500 generic micronase 5mg free shipping, another acid was sought to compete with penicillin for renal secretion blood sugar 140 buy micronase with amex, and probenecid was successfully introduced for this purpose diabetes symptoms for type 1 generic 5 mg micronase mastercard. Because many functions of the kidney are incompletely developed at birth, some xenobiotics are eliminated more slowly in newborns than in adults, and therefore may be more toxic to newborns. For example, the clearance of penicillin by premature infants is only about 20% of that observed in older children. In contrast, some compounds, such as cephaloridine, are nephrotoxic in adult animals but not in newborns. The reduced toxicity results directly from the lack of active uptake of cephaloridine by the kidneys in newborns, such that the chemical is not concentrated in the tubules. The renal proximal tubule reabsorbs small plasma proteins that are filtered at the glomerulus. This largely occurs by pinocytosis at the brush-border membrane of the proximal tubule epithelium. If a toxicant binds to those small proteins, it can be carried into the proximal tubule cells and exert toxicity. Similarly, chemicals such as limonene and 2,4,4-trimethyl pentane bind to the male-rat-specific protein, 2u-globulin, and are taken up by the proximal tubule to produce hyaline droplet nephropathy and eventually renal tumors in male rats (Lehman-McKeeman, 2010). Differences in renal clearance also can occur for compounds filtered at the glomeruli because of differences in plasma protein binding. Similarly, differences in xenobiotic transporter expression, regulation, and function can contribute to differences in the renal excretion of toxicants. Additional factors affecting the excretion of xenobiotics are exemplified by the disposition of griseofulvin in rats and rabbits (Table 5-13). Rabbits metabolize griseofulvin to 6-demethylgriseofulvin (a phase-I metabolite), a low-molecular-weight species that is predominantly excreted in urine. In this example, species differences in biotransformation ultimately determine the route of excretion of griseofulvin. Fecal Excretion Fecal excretion, the second major pathway for the elimination of xenobiotics, is a complex process that is not as well understood as urinary excretion. Nonabsorbed Ingesta In addition to undigested material, varying proportions of nutrients and xenobiotics that are present in food or are ingested voluntarily (drugs) pass through the alimentary canal unabsorbed, contributing to fecal excretion. The physicochemical properties of xenobiotics and the biological characteristics that facilitate absorption were discussed earlier in this chapter. Although most chemicals are lipophilic to some extent and thereby available for absorption, it is rare for 100% of a compound to be absorbed. However, some macromolecules and some high-molecular-weight compounds that are essentially completely ionized are not absorbed at all. For example, the absorption of polymers or quaternary ammonium bases is quite limited in the intestine. Consequently, most of a dose of orally administered sucrose polyester, cholestyramine, or paraquat can be found in feces. The nonabsorbed portion of xenobiotics contributes to the fecal excretion of most chemicals to some extent. One other factor contributing to fecal excretion is intestinal secretion, which likely occurs by passive diffusion out of enterocytes or via exfoliation of intestinal cells during the normal turnover of this epithelium. Biliary Excretion the biliary route of elimination is a significant source contributing to the fecal excretion of xenobiotics and is even more important for the excretion of metabolites. A compound can be extracted by the liver, thereby preventing its distribution to other parts of the body.
There are also competing theories concerning the mechanism of substrate oxidation by P450 compound I (Hrycay and Bandiera diabetes mellitus type 2 case study scribd buy 2.5 mg micronase visa, 2012) diabetic diet popcorn cheap micronase 5 mg otc. This isotope effect is less marked when aromatic hydroxylation proceeds via an arene oxide intermediate blood sugar ketosis purchase micronase amex. Arene oxides are electrophilic and, therefore, potentially toxic metabolites that are detoxified by such enzymes as epoxide hydrolase. Depending on the ring substituents, the rearrangement of arene oxides to the corresponding phenol can lead to an intramolecular migration of a substituent (such as hydrogen or a halogen) from one carbon to the next. In the fourth case, oxygenation of the substrate is followed by a rearrangement reaction leading to cleavage of an amine (N-dealkylation) or an ether (O- and S-dealkylation). Oxygen from P450 compound I is incorporated into the alkyl-leaving group, producing an aldehyde or ketone. In the fifth case, oxygenation of the substrate is followed by a rearrangement reaction leading to loss of a heteroatom (oxidative group transfer). The sixth case, the cleavage of esters and carbamates, resembles heteroatom dealkylation in that the functional group is cleaved with incorporation of oxygen from P450 compound I into the leaving group, producing an aldehyde. In the seventh case, 2 hydrogens are abstracted from the substrate with the formation of a double bond (C=C, C=O, or C=N), with the reduction of oxygen from P450 compound I to water. The hydroxylation of aromatic hydrocarbons may proceed via an oxirane intermediate (ie, an arene oxide) that isomerizes to the corresponding phenol. Alternatively, aromatic hydroxylation can proceed by a mechanism known as direct insertion. The orthoand para-hydroxylation of chlorobenzene proceed via 2,3- and 3,4-epoxidation, whereas meta-hydroxylation proceeds by direct insertion, as shown in. When aromatic hydroxylation involves direct insertion, hydrogen abstraction (ie, cleavage of the In the case of simple, straight-chain hydrocarbons, such as n-hexane, aliphatic hydroxylation occurs at both the terminal methyl groups and the internal methylene groups. In the case of fatty acids (both saturated and unsaturated) and their derivatives (ie, retinoic acid and eicosanoids such as prostaglandins and leukotrienes), aliphatic hydroxylation occurs at the -carbon (terminal methyl group) and the -1 carbon (penultimate carbon), as shown for lauric acid in. Examples of reactions catalyzed by cytochrome P450: hydroxylation of aliphatic carbon. As previously discussed in the section "Epoxide Hydrolases," not all epoxides are highly reactive electrophiles. Although the 3,4-epoxidation of coumarin produces a hepatotoxic metabolite, the 10,11-epoxidation of carbamazepine produces a stable, relatively nontoxic metabolite. Examples of reactions catalyzed by cytochrome P450: hydroxylation of aromatic carbon. N-Hydroxylamines and hydroxyamides are of toxicological interest because under acidic conditions they can dissociate to form reactive nitrenium ions. The dealkylation of xenobiotics containing an N-, O-, or S-methyl group results in the formation of formaldehyde, which can easily be measured by a simple colorimetric assay to monitor the demethylation of substrates in vitro. Seto and Guengerich have shown that the N-demethylation and N-deethylation of N-ethyl-N-methylaniline not only proceed at different rates (with N-demethylation proceeding up to 20 times faster than N-deethylation) but also proceed by different mechanisms (Seto and Guengerich, 1993; Guengerich, 2001a). The mechanism of oxidative deamination is similar to that of N-dealkylation: the -carbon adjacent to the primary amine is hydroxylated, which produces an unstable intermediate that rearranges to eliminate ammonia with the formation of an aldehyde or ketone. Diethyldithiocarbamate methyl ester, a metabolite of disulfiram, also undergoes oxidative desulfuration.
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Glycine stimulates the reaction diabetes symptoms 4 year old boy generic 5 mg micronase with mastercard, probably by removing benzoic acid through conjugation to form hippuric acid diabetic diet options order micronase 5 mg visa. The conversion of androgens to estrogens involves aromatization of the A-ring of the steroid nucleus diabetes prevention program university pittsburgh purchase 2.5 mg micronase overnight delivery. Aromatization of cyclohexane carboxylic acid, a reaction catalyzed by rabbit and guinea pig liver mitochondria. Evidence for the apparent aromatization of a few xenobiotics by other P450 enzyme has also been described. For instance, 19-nortestosterone derivatives can be converted to aromatic metabolites, namely, ethinylestradiol (from norethisterone and norethynodrel) and 7-methylethinylestradiol (from tibolone) (Kuhl and Wiegratz, 2007). Several different peroxidases catalyze the biotransformation of xenobiotics (in addition to performing important physiological functions), and these enzymes occur in a variety of tissues and cell types. However, peroxidases do play an important role in xenobiotic toxicity, especially the activation of drugs associated with idiosyncratic hepatotoxicity, blood dyscrasias (eg, agranulocytosis, neutropenia, aplastic anemia, and thrombocytopenia), and skin rashes, and the activation of xenobiotics (including the activation of proximate carcinogens to ultimate carcinogens) in skin, bladder, bone marrow, and various other extrahepatic tissues. This peroxisomal enzyme catalyzes the disproportionation of hydrogen peroxide to water and oxygen (2H2O2 2H2O + O2). At low concentrations of hydrogen peroxide, catalase can catalyze the oxidation of ethanol. In mammalian peroxidases (in contrast to plant peroxidases), the heme prosthetic group is covalently attached to the enzyme. Iron is bound to 4 pyrrole nitrogen atoms with the nitrogen on the imidazole ring of histidine serving as the usual fifth ligand. This iron-bound oxygen formally contains only 6 (instead of 8) valence electrons, making it a powerful oxidizing species. There is an inverse relationship between the rate of conversion of halides to hypohalous acids and their physiological plasma concentrations: chloride = 100 to 140 mM, bromide = 20 to 100 M, and iodide = 0. This represents an important mechanism of hydrogen peroxide detoxication in saliva, which contains low levels of catalase but high levels (1-5 mM) of thiocyanate, and in the stomach, where the levels of thiocyanate in parietal cells are 3 times greater than plasma levels, which allows gastric peroxidase to inactivate hydrogen peroxide that otherwise stimulates gastric acid secretion by stimulating histamine release from mast cells. The enzyme is inactivated by a variety of ethylenethiourea drugs, such as propylthiouracil and methimazole (which is used as an antithyroid drug in patients with Graves disease), as well as a number of naturally occurring flavonoid/resorcinol compounds that also have antithyroid effects. It can be used as a diagnostic marker to differentiate myeloid leukemia from lymphoid leukemia. When catalyzed by activated neutrophils, ticlopidine oxidation is inhibited by low concentrations of azide and catalase. It is not known whether drugs that cause agranulocytosis are activated in the bone marrow by neutrophils or their precursors that contain myeloperoxidase, or are activated in neutrophils in the general circulation. The formation of phenol and hydroquinone in the liver is also important for myelosuppression by benzene. However, such bone marrow suppression cannot be achieved simply by administering phenol or hydroquinone to mice, although it can be achieved by coadministering hydroquinone with phenol. In certain cases, the oxidation of xenobiotics by peroxidases involves direct transfer of the peroxide oxygen to the xenobiotic, as shown in. Role of cytochrome P450 and peroxidases in the activation of benzene to myelotoxic metabolites. The direct transfer of the peroxide oxygen from a hydroperoxide to a xenobiotic is neither the only mechanism of xenobiotic oxidation by peroxidases nor the most common. Xenobiotics that can serve as electron donors, such as amines and phenols, can be oxidized to free radicals during the reduction of a hydroperoxide.
Transition to postnatal life is a rigorous test in itself diabetes diet for weight loss type 2 buy genuine micronase on line, and severe functional effects may manifest as neonatal mortality diabetes symptoms dark circles under eyes quality 2.5mg micronase. Because of the high restorative growth potential of the mammalian embryo diabete oggi generic 2.5mg micronase with visa, cellular homeostatic mechanisms, and maternal metabolic defenses, mammalian developmental toxicity has generally been considered to be a threshold phenomenon. Assumption of a threshold means that there is a maternal dosage below which no increase in an adverse outcome is elicited. Daston (1993) summarized two approaches for establishing the existence of a threshold. The second approach is to determine whether a threshold exists for the molecular mechanism responsible for the observed effect. Although relatively few mechanisms of abnormal development have been thoroughly studied, it is clear that cellular and embryonic repair mechanisms and dosedependent kinetics both support the plausibility of a mechanistic threshold. Lack of a threshold implies that exposure to any amount of a toxic chemical, even one molecule, has the potential to cause developmental toxicity. Hypothetically, a point mutation in a critical gene could be induced by a single hit or single molecule, leading to a deleterious change in a gene product and consequent abnormal development. This, of course, carries the large assumption that the molecule could traverse the maternal system and the placenta and enter a critical progenitor cell in the embryo. An effect on a single cell might result in abnormal development at the zygote (one-cell) stage, the blastocyst stage (when only a few cells in the inner cell mass are embryo progenitors), or during organogenesis, when organ rudiments may consist of only a few cells. An apparent threshold for developmental toxicity based at least in part on cellular homeostatic mechanisms is demonstrated in studies of mechanisms underlying the teratogenicity of 5-fluorouracil (Shuey et al. For human health risk assessment, it is also important to consider the distinction between individual thresholds and population thresholds. There is wide variability in the human population, and a threshold for a population can be defined as the threshold of the most sensitive individual in the population (Gaylor et al. Indeed, even though the biological target of a developmental toxicant may exhibit a threshold, background factors such as health status or concomitant exposures may render some individuals already at or even beyond the threshold for failure of that biological process. Any further toxic impact on that process, even one molecule, would theoretically increase risk. The concept of thresholds of adversity for reproductive toxicants has recently been reviewed by Piersma et al. Fetal weight is affected at 20 mg/kg and above, whereas incidence of anomalies increases only at 30 mg/kg and above. Anomalies include edema, skull dysmorphology, orbital hemorrhage, wavy ribs, cleft palate, brachygnathia and hindlimb defects. Pathogenesis comprises the cell-, tissue-, and organ-level sequelae that ultimately lead to abnormality. Mechanisms of teratogenesis listed by Wilson (1977) include mutations, chromosomal breaks, altered mitosis, altered nucleic acid integrity or function, diminished supplies of precursors or substrates, decreased energy supplies, altered membrane characteristics, osmolar imbalance, and enzyme inhibition.
The initial target is the medullary interstitial cells diabetes symptoms list order 5mg micronase amex, followed by degenerative changes in the medullary capillaries diabetes symptoms 0f order 5 mg micronase with visa, loops of Henle diabetes mellitus type 2 and exercise purchase micronase 2.5mg online, and collecting ducts (Bach, 1997). Although the exact mechanisms underlying selective damage to the papilla by analgesics are not known, the intrarenal gradient for prostaglandin H synthase activity has been implicated as a contributing factor. This activity is highest in the medulla and least in the cortex, and the prostaglandin hydroperoxidase component metabolizes phenacetin to reactive intermediates capable of covalent binding to cellular macromolecules. The lack of animal models that mimic the papillary injury observed in humans has limited mechanistic research in this area (Schnellmann, 1998). Urinary excretion of enzymes localized in the brush-border (eg, alkaline phosphatase, -glutamyl transpeptidase) may reflect brush-border damage, whereas urinary excretion of other enzymes (eg, lactate dehydrogenase) may reflect more generalized cell damage. Enzymuria is often a transient phenomenon, as chemically induced damage may result in an early loss of most of the enzyme available. In vivo methodologies used to assess renal function and injury have recently been reviewed (Hart, 2010). The simultaneous analysis of cellular metabolites in sera and urine using nuclear magnetic analysis (metabonomics) has matured over the past few years and may provide an additional technology to identify and monitor nephrotoxicity (Coen et al. For example, rats treated with the nephrotoxicant HgCl2 exhibited increased levels of threonine, isobutyric acid, glutamate, and lysine in renal cortical tissue (Wang et al. However, this technology will require further development and validation using different species and renal insults in the presence and absence of underlying diseases prior to greater use. Creatinine is an endogenous compound released from skeletal muscle at a constant rate under most circumstances. Inulin is an exogenous compound that is completely filtered with no reabsorption or secretion. Following the injection of inulin, inulin serum and urinary concentrations and urine volume are determined over time. If creatinine is being used, then serum and urinary creatinine concentrations and urine volume are determined over time. Initially, nephrotoxicity can be assessed by evaluating serum and urine chemistries following treatment with the chemical in question. The standard battery of noninvasive tests includes measurement of urine volume and osmolality, pH, and urinary composition (eg, electrolytes, glucose, and protein). Although specificity is often lacking in such an assessment, urinalysis provides a relatively easy and noninvasive assessment of overall renal functional integrity and can provide some insight into the nature of the nephrotoxic insult. Glucosuria may reflect chemically induced defects in proximal tubular reabsorption of sugars; however, because glucosuria also may be secondary to hyperglycemia, measurement of serum glucose concentrations also must be evaluated. Urinary excretion of high-molecular-weight proteins, such as albumin, is suggestive of glomerular damage, whereas excretion of low-molecular-weight proteins, such as 2-microglobulin, suggests proximal tubular Figure 14-9. It is produced at a constant rate by all tissues, freely filtered by the glomerulus and catabolized by the tubular epithelial cells; thus, its use is limited to serum levels and not urinary levels. Histopathologic evaluation of the kidney following treatment is crucial in identifying the site, nature, and severity of a nephrotoxic lesion. Further, information on the biotransformation and toxicokinetics of the chemical should be used to direct further in vivo and in vitro studies; in particular, what metabolites are found in the kidney and what are the concentrations of parent compound and metabolites in the kidney over time. Once a chemical has been identified as a nephrotoxicant in vivo, a variety of in vitro techniques may be used to elucidate underlying mechanisms (Table 14-3). Tissue obtained from naive animals may be used in the preparation of isolated perfused kidneys, kidney slices, isolated suspensions of renal tubules, cells, or subcellular organelles, primary cultures of renal cells, and established renal cell lines. For example, freshly prepared isolated perfused kidneys, kidney slices, and renal tubular suspensions and cells exhibit the greatest degree of differentiated functions and similarity to the in vivo situation. In contrast, primary cultures of renal cells and established renal cell lines exhibit longer lifespans (>2 weeks), but-by comparison to the in vivo condition-exhibit differentiated functions and similarity to a lesser degree; this is particularly true of immortalized renal cell lines.
