Catecholamines and Hepatic Drug Metabolism

Boobis, Alan Raymond (1974) Catecholamines and Hepatic Drug Metabolism. PhD thesis, University of Glasgow.

Abstract

The thesis embodies work designed to investigate the acute effects of catecholamines on the hepatic metabolism of foreign compounds. Most of the studies were performed on the isolated perfused liver of the rat. The historical development of the techniques used in the perfusion of the liver is reviewed. The literature concerning the properties of the hepatic mixed function system responsible for the metabolism of foreign compounds has been reviewed. Previous work on the effects of catecholamines on drug metabolism is also discussed. The operative procedure and the technique for the perfusion of the liver were developed to enable rapid transfer of the liver to the perfusion chamber without a period of anoxia, which has characterised many previous attempts at perfusion of the liver. The liver was perfused with a semisynthetic medium. The viability of the liver was assessed by a variety of tests of biochemical and physiological function and by histological examination. The technique developed allowed the liver to be successfully perfused for periods of up to 6 h, whilst maintaining a functional integrity. The metabolism of the type I and the type II substrates, hexobarbitone and aniline respectively, were investigated. Hexobarbitone is removed by a first order reaction at a rate comparable to that previously reported for the liver in vivo. Aniline metabolism, which has not previously been investigated in the perfused liver, was studied in some detail. Aniline is removed biphasically from the perfusion medium. Half of the aniline removed is converted to an acid-labile conjugate, possibly aniline-N-glucuronide, and a further 25% is converted to p-aminophenol and its conjugates. 3H-aniline added to the perfused liver could be quantitatively accounted for after 3 h perfusion. In agreement with previous findings, it was found that p-aminophenol reacts with haemoglobin, thus making it impossible to detect free p-aminophenol in the perfusion medium. The differences between the pattern of aniline metabolism by the perfused liver and by the whole animal, where aniline is excreted mainly as p-aminophenol and its conjugates, are discussed. The kinetics of aniline removal have been analysed by curve stripping and model fitting. The mathematics of these procedures are described separately in Appendix II. In the perfused liver aniline is distributed throughout a two-compartment system. The first compartment probably represents the total aqueous phase and aniline is removed from this compartment only. The identity of the second compartment is less certain. Several possibilities are discussed and in view of evidence obtained with SKF 525-A, an inhibitor of drug metabolism, it is suggested that the second compartment may represent the binding of aniline to a non-metabolic site of cytochrome P-450. Both adrenaline and noradrenaline inhibit the metabolism of hexobarbitone by the perfused liver but neither catecholamine has any effect on the metabolism of aniline. Catecholamines do not inhibit the metabolism of either aniline or hexobarbitone by the microsomal fraction or by liver slices. It was thus concluded that catecholamines are not inhibiting hexobarbitone removal directly. The possibility that their effect is mediated by cyclic AMP, a compound reported to inhibit hexobarbitone metabolism by the perfused liver, was investigated. Papaverine, an inhibitor Of phosphodiesterase, does not potentiate the inhibitory effects of catecholamines on hexobarbitone metabolism, nor does it cause them to have any inhibitory effect on the metabolism of aniline. Cyclic AMP was shown to inhibit drug metabolism by liver slices, whereas catecholamines are without effect. The probability that cyclic AMP is not important in mediating the effects of catecholamines on drug metabolism is discussed in some detail. Both catecholamines increase the portal pressure in the -perfused liver by over 100%. When Ca2+ is omitted from the perfusion medium it was found that this pressor effect is almost totally inhibited. Catecholamines also no longer in- hibit the metabolism of hexobarbitone. The omission of Ca2+ leaves the metabolic effects of catecholamines relatively unaffected. It was thus suggested that catecholamines might be inhibiting hexobarbitone metabolism through an effect on the hepatic vasculature. In a constant flow system, as used in this study, one way in which such an effect of catecholamines might manifest itself is as a redistribution of perfusate through the liver. It was found that considerable controversy exists as to whether or not catecholamines can cause a redistribution of blood flow within the liver. The available evidence is assessed separately in Appendix II. The effects of adrenaline on the intrahepatic distribution of perfusate have been investigated by X-radiography, and by perfusing the liver with Indian ink followed by histology. It was concluded from these studies that catecholamines can cause a redistribution of blood flow within the liver, away from the periphery of the lobes towards more central regions. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology, Physiology
• Date of Award: 1974
• Depositing User: Enlighten Team
• Unique ID: glathesis:1974-78663
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 15:04
• Last Modified: 30 Jan 2020 15:04
• URI: https://theses.gla.ac.uk/id/eprint/78663