This title is available in both hardbound and paperback editions. The paperback edition is sold subject to the condition that it shall not, by way of trade or otherwise, be lent, resold, hired out, or otherwise circulated without the publisher's prior consent in any form of binding or cover other than that in which it is published and without a similar condition including this condition being imposed on the subsequent purchaser.All rights reserved. No part of this book may be reprinted, or reproduced or utilized in any form or by an electronic, mechanical or other means, now PrefaceAlthough the scientific literature on drug metabolism is extensive, it suffers from the disadvantage that the material is diffuse and consists largely of specialist monographs dealing with particular aspects of the subject. In addition, although there are a few excellent texts on drug metabolism in print, these tend to be earlier publications and hence do not take into account the many recent advances in this area. Our motivations for writing this book therefore arose from the clear need for a recent and cohesive introductory text on this subject, specifically designed to cater for the needs of undergraduate and postgraduate students. Much of the subject matter in this text is derived from various courses on drug metabolism given at the University of Surrey and the University of Glasgow to basic science students in pharmacology, biochemistry, nutrition and nursing studies, to pre-clinical medical students and to undergraduate and post-graduate students in toxicology. Therefore, it is our intention that this text will serve as a primer in drug metabolism to a variety of students in the life sciences taking courses in this subject.The term 'drug metabolism' in its broadest sense may be considered as the absorption, distribution, biotransformation and excretion of drugs. To cover all these facets of drug metabolism in a single text is a voluminous task and therefore we have focused primarily on the biotransformation aspects of the subject. Having said this, the text is not solely a list of drug metabolism pathways, but rather it uses biotransformation reactions to rationalize many ix some of their published material. Finally, we express our thanks to the staff of Chapman and Hall for their excellent co-operation and for giving us the opportunity to bring this project to fruition.
Sex differences exist in steroid and xenobiotic metabolism in the liver of a number of species. In the rat, the differences are regulated through the hypothalamo-pituitary axis. The previously postulated "feminizing factor" responsible for a female-type liver metabolism appears to be identical to growth hormone. The different effects of this peptide on hepatic metabolism in male and female rats may be related to the sexual dimorphism of the growth hormone secretory pattern; serum levels of growth hormone do not fluctuate as markedly in female as in male rats and may be simulated by administration of the hormone via osmotic minipumps, a procedure resulting in "feminization" of liver metabolism of male or hypophysectomized rats. This newly discovered system, the hypothalamo-pituitary-liver axis, represents a novel concept in endocrinology.
Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families or subfamilies in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.
Antibodies to rat prolactin were used in immunohistochemical studies of the hypothalamus and preoptic area of the rat. Evidence was obtained that a protein immunochemically related to prolactin was stored in networks of nerve terminals of many hypothalamic areas such as the arcuate nucleus, the dorsomedial hypothalamic nucleus, and periventricular regions of the hypothalamus and preoptic area. The neuronal storage of a prolactin-like protein in the hypothalamus was unaffected by hypophysectomy.
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