Table 1.
Notable advances between 1932 and 1995 in shaping the field of pharmacogenetics.a
| Observation | Key Reference |
|---|---|
| Phenylthiourea (PTU) nontaster traitb | (Snyder, 1932) |
| Glucose-6-phosphate dehydrogenase (G6PD) deficiency | (Alving et al., 1956) |
| N-acetylation (NAT) polymorphism | (Knight et al., 1959; Evans et al., 1960) |
| Federation Proceedings of the Am. Soc. Exp. Biologists (FASEB): two symposia gave high visibility to the field. | (Kalow, 1965; O'Reilly and Aggeler, 1965; Armaly and Becker, 1965; Wigle, 1965; La Du, 1965; Eichelbaum, 1984; Spielberg, 1984; Vesell, 1984; Weber, 1984; La Du and Eckerson, 1984; Vesell and Penno, 1984; Weinshilboum, 1984a; Kalow, 1984a; Weinshilboum, 1984b; Kalow, 1984b) |
| Genetic variation in ethanol metabolism; mutation in aldehyde dehydrogenase (ALDH) gene | (Von Wartburg et al., 1964) |
| The aryl hydrocarbon receptor and [Ahr] gene battery | (Nebert et al., 1975) |
| Debrisoquine/sparteine oxidation polymorphism (CYP2D6 gene) | (Mahgoub et al., 1977; Eichelbaum et al., 1979) |
| Thiopurine methyltransferase (TPMT) gene polymorphism | (Weinshilboum and Sladek, 1980) |
| Identification of the human GSTM1 null allele; GSTT1 null allele later | (Seidegård et al., 1986) |
| Molecular cloning of the CYP2D6 gene and variant alleles | (Gonzalez et al., 1988) |
| Molecular cloning of the NAT2 gene and variant alleles | (Blum et al., 1990) |
| Molecular cloning of the CYP2C19 gene and variant alleles | (Goldstein and de Morais, 1994) |
| Molecular cloning of the TPMT gene and variant alleles | (Krynetski et al., 1995) |
Detailed in (Nebert, 1997); please see this Opinion Article to find additional discussion and other relevant studies and references. Just as monogenic disorders in human genetics are proposed to involve genes encoding “moonlighting” enzymes having more than one function (Sriram et al., 2005), so have all xenobiotic-metabolizing enzymes (XMEs) been proposed to carry out endogenous functions—in addition to functions of metabolizing a drug or environmental toxicant (Nebert, 1991;Nebert and Dalton, 2006).
The taste receptor gene TAS2R1 was identified 70 years later (Kim et al., 2003) as responsible for the PTU nontaster trait. Contrary to the XME and XRT genes, such a receptor polymorphism more likely is inherited as a monogenic human disease than as an hPpM pharmacogenetic disorder.