Differences in hepatic drug accumulation and enzyme induction after chronic amiodarone feeding of two rat strains: role of the hydroxylator phenotype?

Pirovino, M; Honegger, Ulrich E.; Müller, Otfried; Zysset, Thomas; Küpfer, A; Tinel, Marina; Pessayre, Dominique

doi:10.1111/j.1476-5381.1990.tb14650.x

Cited by 7 publications

(2 citation statements)

References 23 publications

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“…Strain-related differences in the biotransformation to desethylamiodarone may account for the observe d differences in response to amiodarone. In a recent study, Pirovino et al (1990) clearly demonstrated that the amiodarone-induced pulmonary phospholipidosis was associated w ith a significant increase in the activities of hepatic microsomal cytochrome P-450 and NADPH cytochrome c reductase, and with an elevation in serum desethylamiodarone in DA strain rats. In contrast, a lack of effect on morphology and phospholipid content was accompanied by no marked change in the microsomal mixed-function oxidase system in am iodarone-treated Sprague-D aw ley rats.…”

Section: Lungmentioning

confidence: 97%

Editorial

Kacew

Festing²

1996

Journal of Toxicology and Environmental Health

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The development of drugs to combat diseases, chemicals to improve food production, or compounds to enhance the quality of life necessitates, by law, the use of laboratory animals to test their safety. In order to simulate the human condition it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms are established and resemble those of humans. The advantages of the use of the rat in drug and chemical toxicity testing include (a) metabolic pathway similarities to humans; (b) numerous similar anatomical and physiological characteristics; (c) a large database, which is extremely important for comparative purposes; and (d) the ease of breeding and maintenance of animals at relatively low cost. However, the choice of rat can be complicated, especially when over 200 different strains of rat are known to exist. The aim of this review is to summarize genetically determined differences in the responsiveness of rat strains to drugs and naturally occurring chemicals and to show that susceptibility is dependent on the target organ sensitivities, which may also be strain dependent. It is suggested that detailed studies of strain differences may help to clarify toxic mechanisms. Such studies are usually best conducted using inbred strains in which the genetic characteristics have been fixed, rather than in outbred stocks in which individual samples of animals may differ, the phenotype is variable, and the stocks are subject to substantial genetic drift. The fact that strains may differ also needs to be taken into account in assessing the potential hazard of the chemical, particularly when a study involves only a single strain and therefore provides no assessment of likely strain variation.

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Section: Lungmentioning

confidence: 97%

Editorial

Kacew

Festing²

1996

Journal of Toxicology and Environmental Health

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“…Rats are the most common laboratory model for investigating vitamin A metabolism. However, inter-strain differences in both vitamin A metabolism and responsiveness to drug administration are known to exist among rats, making extrapolation of data from one strain to another difficult (Pirovino et al 1990;Seifert et al 1991;Lahmame & Armario, 1996;Tuitoek et al 1996;Schindler et al 2002). Therefore, another factor considered when designing the present study was the rat strain.…”

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confidence: 99%

Flupenthixol and cefotiam: effects on vitamin A metabolism in rats

2004

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We examined the alterations in vitamin A metabolism as a result of flupenthixol or cefotiam administration. The impact of these drugs on indices of vitamin A status was evaluated in Brown Norway and Long -Evans rats. Intramuscular drug administration for 28 d resulted in a decline in systemic retinol. Changes in circulating retinol with time for chronic dosing showed drug treatment (P, 0·001) and time (P, 0·03) to be significant factors, but rat strain (P¼0·33) was not a significant factor. Flupenthixol was the most active retinol-lowering compound (P, 0·005). At the end of the 28 d period, hepatic retinyl ester hydrolase activity was greater in drug-treated rats than in controls (P, 0·05). With regard to effects on liver reserves: (1) flupenthixol treatment resulted in vitamin A depletion (P, 0·05); (2) cefotiam treatment stimulated vitamin A accumulation; (3) distinctive patterns of retinol and its esters were seen in response to treatment. It is reasonable to assume that the drugs interfere with vitamin A in at least two ways: (1) lowering of plasma retinol, an early event in the interaction, may be caused by inhibition of hepatic holo-retinol-binding protein secretion or stimulation of clearance, or both; (2) when plasma retinol levels are persistently low, and as the hepatic deposits of the xenobiotics build up, there are changes in the vitamin A pool size and composition of the liver. Candidate enzymes are retinyl ester hydrolase and cytochrome P450. The relationship between these two events will be studied in further detail. Flupenthixol -vitamin A interaction: Cefotiam -vitamin A interaction: Retinyl ester hydrolase

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Lysosome Dysfunction: An Emerging Mechanism of Xenobiotic‐Induced Toxicity

Jessen

Will

et al. 2016

Lysosomes: Biology, Diseases, and Therapeutics

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Differences in hepatic drug accumulation and enzyme induction after chronic amiodarone feeding of two rat strains: role of the hydroxylator phenotype?

Cited by 7 publications

References 23 publications

Editorial

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Flupenthixol and cefotiam: effects on vitamin A metabolism in rats

Lysosome Dysfunction: An Emerging Mechanism of Xenobiotic‐Induced Toxicity

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