Drug metabolism and hepatotoxicity.

Drug metabolism in the 1960s At the time the Liver Unit was established in 1966, interest in the study of drug metabolism was growing, stimulated largely by the pharmaceutical industry, and the legislative requirements imposed upon it. It represented a remarkable change from the situation a few years previously when'. . . the study ofthe metabolism of foreign compounds was not a popular one; biochemists considered it rather a waste of time and effort, both of which could be better expended on looking at naturally occurring substances. Pharmacologists also had little interest in the subject and regarded it as unrelated to their immediate problems. Toxicology was in a primitive state of development and still largely concerned with cataloguing and describing the effects of various poisons'.' By the 1960s, however, centres in Britain, Europe, and the United States had begun to characterise the drug metabolising enzymes and their responses to repeated drug ingestion. In 1966, novel discoveries emphasised: (i) the existence of more than one form of cytochrome P-450,2 the basic function3 and characterisation45 of which had been defined only in the previous three years; (ii) the clinical implications ofenzyme induction to drug therapy, as illustrated by three case reports, one describing fatal haemorrhage after withdrawal of the enzyme inducing sedative chloral hydrate in a patient on anticoagulants,' and two showing relief of paediatric jaundice with phenobarbitone; 8 (iii) the hepatotoxicity ofenvironmental toxins, after the outbreak of Epping jaundice resulting from contamination of flour with 4,4diamino-diphenylmethane.9 The limited understanding of the mechanisms of hepatotoxic drug reactions at that time can be gauged from a 1969 review by Schaffner and Raisfeld."' An abundance of important interactions between chemicals and endogenous biochemical pathways had been documented, however, as exemplified in the review ofcarbon tetrachloride hepatotoxicity by Recknagel" which continues to complement contemporary texts. 12 In 1967 Conney published his almost timeless review of the agents responsible for enzyme induction in which he predicted that 'the genetic make-up ofthe individuals ofa population within a given species may be important in determining the occurrence or magnitude of enzyme induction'.'3 Support for these prophesies was some years away, but the monitoring ofenzyme induction in man and its clinical features and benefits was the starting point for the King's Liver Unit Drug Metabolism Group in 1966. Studies on the clinical value of phenobarbitone in the treatment ofunconjugated hyperbilirubinaemia dominated the late 1960s 1116 and prompted the search for alternative inducing therapies with fewer hypnotic side effects."' In 1965 Aarts" had suggested that urinary glucaric acid excretion might reflect hepatic drug metabolising enzyme activity. Over the next five years interest at King's centred around screening for enzyme induction by measuring the urinary excretion of this compound.'9 The test was validated by showing an association with hepatic cytochrome P-450 content,20 and was used to show the enzyme inducing properties ofdrugs2' and environmental contaminants such as DDT.22 The observation that urinary D-glucaric acid excretion rose during the course of normal pregnancy indicated that changes in hepatic microsomal enzyme activity could be associated with endogenous compounds and physiological states.23 Other studies showed a correlation between urinary D-glucaric acid excretion and low circulating levels of calcium and folic acid in epileptic patients.2425 This prompted the suggestion that the enzyme inducing properties of anticonvulsant drugs could lead to increased consumption and eventual deficiency of vitamin D and folic acid.