Genetic Polymorphisms in Human Drug-Metabolizing Enzymes: Potential Uses of Reverse Genetics to Identify Genes of Toxicological Relevance

Abstract

The human mind was engaged with fundamental questions on the nature of heredity long before the study of genetics became a scientific discipline. Many traits, such as height, eye color, blood pressure, or cancer susceptibility, have been known to run in families, although the genes or combination of genes that underlie these observable characteristics remain unknown in most cases. Differences in susceptibility to environmental agents in humans are likewise determined by variations in genetic background--genetic polymorphisms. In this article, we review the current status of studies on human polymorphisms in drug-metabolizing enzymes and discuss various approaches to the analysis of genetic polymorphisms. We expect that in the near future, novel methods in genetic analysis of human populations will be likely to play a key role in the identification of genes of toxicological relevance.

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

“…Genetic polymorphisms in genes encoding CYP2E1, MPO, NQO1, and GSTs (Hirvonen et al 1993;Piedrafita et al 1996;Puga et al 1997;Traver et al 1997) might be responsible for human susceptibility to BP because they might have an effect on enzyme activity. NQO1 with a C-to-T substitution in cDNA at nucleotide 609 (NQO1 c.609C>T variation) causes reduced or lost enzyme activity (Traver et al 1992).…”

Aromatic Hydrocarbon Receptor Polymorphism: Development of New Methods to Correlate Genotype with Phenotype

“…CYPlAl inducibiity varies by more than 30-fold in humans (20)(21)(22)(23), and Scatchard plot analyses of 106 human placental samples have shown a >35-fold difference in AHR affinity between the highest and lowest phenotype (24,25), yet there has not been any direct correlation established between the degree of CYPlA1 inducibility and the variation in AHR affinity in humans nucleotide or amino acid change in the human AHR has been unequivocally associated with ligand variability. Substitution of alanine for valine at position 381 (equivalent to position 375 in the mouse) was shown to increase ligand affinity several-fold in an in vitro cDNA-expression binding assay (15); however, the human AHR protein from the HepG2 and A431 cell lines, as well as from at least eight individuals, contains valine at position 381 in all cases (15,22,26- (Fig.…”

“…The existence of a human AHR polymorphism to explain the observed variability in CYPlAI inducibility (20)(21)(22) and AHR affinity (2426) has been hypothesized for many years; however, conclusive evidence to demonstrate this putative polymorphism is lacking (23,37,38). Among the B6, D2, C3H, and Mus spretus mouse lines, there are 12 AHR amino acid differences (9)(10)(11)(12)(13)(14)(15).…”

Estudo de fase II avaliando eficácia e toxicidade de UFT (uracil e tegafur) e leucovorin, administrados duas vezes ao dia, no tratamento de pacientes com câncer metastático de cólon e reto

“…Esse é um importante gene supressor de tumores, e sua ausência quase sempre causa o aparecimento de centenas a milhares de pólipos, começando na puberdade 31,32 . Se o cólon e o reto de pacientes portadores dessa doença não forem removidos, a evolução para câncer é praticamente certa, embora exista hoje medicação disponível para reduzir o número de pólipos em pacientes portadores dessa síndrome 33 . O uso do celecoxib, um inibidor específico da enzima ciclooxigenase-2, diminui a incidência de pólipos nesses pacientes, mas a ressecção cirúrgica permanece como tratamento padrão 33 .…”

“…Se o cólon e o reto de pacientes portadores dessa doença não forem removidos, a evolução para câncer é praticamente certa, embora exista hoje medicação disponível para reduzir o número de pólipos em pacientes portadores dessa síndrome 33 . O uso do celecoxib, um inibidor específico da enzima ciclooxigenase-2, diminui a incidência de pólipos nesses pacientes, mas a ressecção cirúrgica permanece como tratamento padrão 33 . Felizmente essa síndrome é incomum e dá origem a um número pequeno de casos de câncer anualmente.…”