Xenobiotic metabolism: a look from the past to the future.

The earliest history of xenobiotic metabolism is interwoven with the birth of organic chemistry. In the early 1800s, the belief prevailed that the composition of the human body and indeed, of all living things, was a result of a “vital force” or “internal flame” and that mere mortals were incapable of understanding these workings and would be particularly unable to synthesize constituent compounds of the human body. Friedrich Wöhler (Wöhler and Frerichs, 1848) shattered this myth with the test tube synthesis of the human excretion product, urea. Wöhler’s thinking led to the first metabolism experiments demonstrating the conjugation of benzoic acid with glycine in man (Ure, 1841; Keller, 1842). The transformation of compounds like cinnamic acid (Erdmann and Marchand, 1842) and benzaldehyde (Wöhler and Frerichs, 1848) to benzoic acid indicated the ability of the body to oxidize ingested compounds, which was further emphasized by the discovery by Schultzen and Naunyn (1867) of the conversion of benzene to phenol. The early descriptions of conjugation were exemplified by Baumann’s determination that “indigo-forming substance” was actually the corresponding sulfate conjugate (Baumann, 1876). Baumann’s lab was also involved in the initial identification of mercapturic acids as elimination products (Baumann and Preuss, 1879). Schmiedeberg and Meyer (1879) characterized the conjugate of camphor as a glucuronide. Methylation was initially described by His (1887), while acetylation reactions were elaborated by Cohn and coworkers (1893). Lautemann and colleagues (1863) ingested calcium quinate to demonstrate its reduction to benzoic acid and excretion as hippuric acid. Hoppe-Seyler published the first paper on nitro reduction in 1882 (Hoppe-Seyler, 1882). The potential impact of metabolism on drug therapy was dramatically demonstrated in the development of the antibiotic prontosil (Domagk, 1935). The reduction of this compound to sulfanilamide provided a breakthrough in antibiotic therapy and demonstrated the role of metabolism in producing active metabolites (Trefouél et al., 1935; Fuller, 1937). Many individual investigations over the first 100 years of metabolism research led to the classic compilation of R.T. Williams “Detoxification Mechanisms” in 1947 (Williams, 1947). This tome heralded the birth of xenobiotic/drug metabolism as a distinct branch of science. Biochemical research in the early 1950s unveiled the mechanisms of a wide variety of transformation reactions. The pioneering studies of James and Elizabeth Miller and Julius Axelrod revealed the subcellular localization of metabolism reactions and the identification of the enzymes responsible for catalysis of the transformation (Mueller and Miller, 1949; Axelrod, 1955). The discovery of the role of cytochrome P450 in metabolism by Omura and Sato (1962) and Estabrook, Cooper, and Rosenthal (1963) was an invitation to scientists from many peripheral disciplines to take an interest in metabolic transformations. In the clinical setting, the discovery of the genetic polymorphism involved in debrisoquine (Mahgoub et al., 1977) and sparteine (Eichelbaum et al., 1978) metabolism and the presence of isozymes of cytochrome P450 (Thomas et al., 1976) and other metabolizing enzymes emphasized the importance of individual response to drugs. Our understanding of control of enzyme synthesis, transcription of DNA, and molecular mechanisms of cellular control has been greatly enhanced by the study of the body’s response to foreign compounds. The rapidly accelerating pace of scientific discovery, exemplified by the sequencing of the human genome, foretells the increasingly important role of metabolism in designing individual drug therapy. The drug industry has routinely targeted the average individual for therapy, while it has become increasingly clear that all patients are unique in both their pharmacokinetic and pharmacodynamic response to drugs. Monitoring individual pharmacokinetic and pharmacodynamic response will be the challenge of modern pharmacotherapy. Knowledge of individual characteristics including genetic inheritance, phenotypic expression, concomitant therapy, age, sex, and other physiological factors can all help to predict the disposition of new drugs. The alternative approach of measuring levels of drugs in the individual patient also clearly has potential. If we think of drugs at molecular levels rather than weight per volume, the challenge becomes clear. Thus, a picomole per milliliter plasma level sounds quite low, but when one realizes that this represents a level of one billion molecules/ml there is much room for advanced analytical techniques. Biological systems have the ability to specifically recognize individual molecules and by enzymatic amplification convert the recognition into an electronic signal. Harnessing our growing insight into biochemical mechanisms to monitor drug exposure may provide the breakthrough necessary for truly individualized therapy. The combination of our advanced understanding of metabolism with modern diagnostic techniques including genomics and proteomics will allow the generation of individualized paradigms for the treatment of disease. Drug metabolism scientists are uniquely positioned to bring about this revolution in individual therapy. We are finally approaching the goal of xenobiotic metabolism research as stated by Marcel Nencki in 1870 whereby “one will on the one hand be able to establish Adapted from a Plenary Lecture presented at the 10 North American meeting of the International Society for the Study of Xenobiotics (ISSX), October 24–28, 2000, Indianapolis, Indiana.