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At least 685 records · Page 38Linked to original sources
PubMed1989

A model of cytochrome P-450-centered hepatic dysfunction in drug metabolism induced by cobalt-protoporphyrin administration.

Cobalt-protoporphyrin treatment disrupts cytochrome P-450-centered drug metabolism and is known to decrease significantly the cytochrome P-450 content of the liver. This study assesses further the correlations between biochemical and functional changes induced by Co-protoporphyrin. Specifically, it confirmed the fall in cytochrome P-450 levels in liver and demonstrated that both NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase activities decreased in a dose-dependent manner, albeit to a lesser degree, upon Co-protoporphyrin administration. Furthermore, plasma clearance of the marker drug aminopyrine fell off abruptly with a minimal decrease in cytochrome P-450 content, and then monotonically with its further depletion. Both aminopyrine and caffeine demethylation, as measured by the amount of radiolabeled CO2 exhaled, also decreased with diminishing cytochrome P-450 content. With aminopyrine the decrease was abrupt but with caffeine biphasic, consistent with preferential isozyme depletion. The drop in oxidative drug metabolism measured by these two in vivo techniques occurred in the absence of organellar damage to hepatocytes, as observed by electron microscopy. In vitro studies of aminopyrine metabolism in microsomes prepared from rats with and without Co-protoporphyrin injection proved to be consistent with the in vivo studies. Moreover aminopyrine Vmax decreased and Km increased with decreasing cytochrome P-450 content, suggesting preferential isozyme depletion. Furthermore, the changes in aminopyrine intrinsic clearance predicted by the in vitro Vmax and Km values agreed with those measured by in vivo plasma clearance. Taken together, these data suggest that Co-protoporphyrin treatment can be used to produce a model of altered cytochrome P-450-centered drug metabolism, as measured consistently by several techniques. However, this model appears to be more complex than one involving nonspecific depletion of cytochrome P-450 alone, and may be influenced also by concomitant changes in the electron transport chain or other aspects of hepatic metabolism.

Aminopyrine↗
PubMed1983

Pesticide-induced dysfunction in carbohydrate metabolism in three freshwater fishes.

In the present investigation, the effect of sublethal fractions (1/4th, 1/8th and 1/16th of 96-hr LC50) of thiotox and dichlorvos on blood glucose, lactate, and liver and muscle glycogen levels of Clarias batrachus, Saccobranchus fossilis, and Mystus vittatus, exposed for 30 days, have been studied. It was observed that blood glucose and lactate levels increased from 29.13 to 98.36% and from 10.88 to 36.36%, respectively. The liver and muscle glycogen decreased from 22.99 to 69.30% and from 5.19 to 32.19%, respectively. The reasons for this carbohydrate imbalance have also been suggested.

Animals↗
PubMed1983

Uteroplacental dysfunction and prostaglandin metabolism in zinc deficient pregnant rats.

Relationships between perinatal mortality, disrupted utero-placental function and prostaglandin metabolism have been studied in Zn-deficient rats. Uterine contractility in vitro, placental blood flow in vivo, and uterine and placental prostaglandin synthesis from [1-14C] arachidonic acid in vitro were investigated at day 22 of pregnancy. High amplitude uterine contractions were almost completely eliminated and utero-placental blood flow was decreased by 85% by Zn deficiency. Synthesis of [1-14C]-prostaglandin E2, F2 alpha and 6-keto-F1 alpha from [1-14C] arachidonic acid decreased significantly in uterine tissue but increased in placentae. These possibly inter-related effects may contribute to the high perinatal mortality observed in Zn deficiency.

Animals↗
PubMed2004

A single dose of nateglinide improves post-challenge glucose metabolism and endothelial dysfunction in Type 2 diabetic patients.

AIMS: This randomized crossover placebo-controlled study aimed to assess the efficacy of nateglinide, a phenylalanine-derived insulin secretagogue, on forearm endothelial function in diabetic subjects before and after an oral glucose load. METHODS: Forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperaemia before and after an oral glucose load (75 g) with a prior use of placebo or nateglinide (90 mg) in 15 diet-treated Type 2 diabetic patients or age-matched controls with normal glucose tolerance. RESULTS: The peak FBF response and total reactive hyperaemic flow (flow debt repayment: FDR), indices of resistance artery endothelial function, were decreased after an oral glucose load in diabetic patients, but unchanged in controls. Nateglinide administered to diabetic patients accelerated insulin secretion and reduced post-challenge plasma glucose, and also abolished the post-challenge impairment of endothelial function. The peak FBF and FDR were well correlated with 120-min glucose levels and 30-min insulinogenic index. CONCLUSIONS: A single challenge of glucose was shown to impair endothelial function in diabetic patients, and the post-challenge endothelial dysfunction was improved by a prior use of nateglinide. Long-term effects of nateglinide on endothelial function in Type 2 diabetic patients need to be clarified in future studies.

Administration, Oral↗
PubMed2005

Contractile dysfunction and altered metabolic profile of the aging rat thyroarytenoid muscle.

The larynx and its muscles are important for ventilation, coughing, sneezing, swallowing, Valsalva's maneuver, and phonation. Because of their functional demands, the intrinsic laryngeal muscles have a unique phenotype: very small and fast fibers with high mitochondrial content. How aging affects their function is largely unknown. In this study, we tested the hypothesis that an intrinsic laryngeal muscle (thyroarytenoid muscle, a vocal fold adductor) would become weaker, slower, and fatigable with age. Muscles from Fischer 344 x Brown Norway F1 hybrid rats (6, 18, and 30 mo of age) were used for in vitro contractile function and histology. Thyroarytenoid muscles generated significantly lower twitch and tetanic forces at 30 mo vs. 6 and 18 mo. Maximal shortening velocity decreased by 20% at 30 mo (vs. 6 mo), and velocity of unloaded shortening was slower at 18 and 30 mo by 19 and 27% vs. 6 mo. There was no histochemical evidence of altered myosin ATPase activity at 18 or 30 mo of age. Fatigue resistance was significantly decreased at 18 and 30 mo. We also found abundant mitochondrial clusters and ragged red fibers in the muscles of 30-mo-old rats, and there was an age-related increase in glycogen-positive fibers. We conclude that rat thyroarytenoid muscles become weaker, slower, and more fatigable with age. These functional changes are not due to alterations in myosin ATPase activity, but a switch in the expression of myosin isoforms remains a possibility. Finally, the alterations in mitochondrial and glycogen content indicate a shift in the metabolic characteristics of these muscles with age.

Aging↗
PubMed1988

Effect of rapid normalization of plasma glucose levels on microvascular dysfunction and polyol metabolism in diabetic rats.

Effects of rapid normalization of plasma glucose levels (by insulin infused via Alzet pumps implanted intraperitoneally) on plasma insulin-like growth factor I (IGF-I) levels, granulation tissue polyol levels, and vascular permeation by 125I-labeled albumin were examined in male Sprague-Dawley rats with streptozocin-induced (60-65 mg/kg) diabetes. Two days after implantation of pumps, plasma insulin levels were twice normal levels and remained elevated (1.4-2.5 times normal) throughout the remainder of the study. Plasma glucose levels and granulation tissue polyol levels were normalized within 2 days after initiation of insulin treatment. Plasma IGF-I levels were significantly increased (2 times) by 2 days, but were not normalized until 7 days. In contrast, 125I-albumin permeation normalized at a much slower relatively linear rate and was still not completely normal after 14 days of insulin treatment. In view of 1) previous studies demonstrating that diabetes-induced increases in 125I-albumin permeation in this tissue are linked to increased metabolism of glucose to sorbitol and 2) the rapid normalization of tissue polyol levels in this study, the relatively linear rate of normalization of vascular permeability over 14 days in these studies suggests that impaired vascular barrier functional integrity in this model is mediated by structural and/or functional vascular alterations associated with sustained increased polyol metabolism rather than by increased polyol levels per se and/or by readily reversible functional and metabolic alterations associated with acute increases in polyol metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗