Pharmacogenetics: detecting sensitive populations.

Abstract

Risk assessment models strive to predict risks to humans from toxic agents. Safety factors and assumptions are incorporated into these models to allow a margin of error. In the case of cancer, substantial evidence shows that the carcinogenic process is a multistage process driven by the interaction of exogenous carcinogenic exposures, genetic traits, and other endogenous factors. Current risk assessment models fail to consider genetic predispositions that make people more sensitive or resistant to exogenous exposures and endogenous processes. Several cytochrome P450 enzymes, responsible for metabolically activating carcinogens and medications, express wide interindividual variation whose genetic coding has now been identified as polymorphic and linked to cancer risk. For example, a restriction fragment-length polymorphism for cytochrome P4501A1, which metabolizes polycyclic aromatic hydrocarbons, and cytochrome P4502E1, which metabolizes N-nitrosamines and benzene, is linked to lung cancer risk. Cytochrome P4502D6, responsible for metabolizing many clinically important medications, also is linked to lung cancer risk. The frequency for each of these genetic polymorphisms vary among different ethnic and racial groups. In addition to inherited factors for the detection of sensitive populations, determining the biologically effective doses for carcinogenic exposures also should quantitatively and qualitatively enhance the risk assessment process. Levels of carcinogen-DNA adducts reflect the net effect of exposure, absorption, metabolic activation, detoxification, and DNA repair. These effects are genetically predetermined, inducibility notwithstanding. The combination of adduct and genotyping assays provide an assessment of risk that reflects recent exogenous exposure as well as one's lifetime ability to activate and detoxify carcinogens. -Environ Health Perspect 102(Suppl 1 1):81-87 (1994)

Cellular and humoral immune abnormalities in Gulf War veterans.

“…Based on these observations and earlier reports by others, we believe that GWS is a multifactorial disease caused by exposure to a variety of environmental conditions, for example, xenobiotics, vaccinations, and other stressor-related conditions of the Gulf War environment as summarized in Figure 3. We believe that the outlined multiple factors along with genetic susceptibility due to polymorphism of PON1, loss of neuropathy target esterase, glutathione S-transferase, cytochrome P450 enzymes, or other factors may affect some individuals, resulting in immune dysregulation (Haley et al 1999;Loewenstein-Lichtenstein et al 1995;Shields 1994;Whatt et al 2000). These immune functional alterations reported herein may cause viral reactivation and induction of proinflammatory cytokines, resulting in symptoms similar to those of chronic fatigue and fibromyalgia, as well as other symptoms of GWS (Ferguson andCassaday, 2001/2002;Patarca 2001;Rook and Zumia 1997;Zhang et al 1999).…”

Challenges Identifying Genetic Determinants of Pediatric Cancers – the Childhood Leukemia Experience

“…The CYP1A1 variants *2A and *2B, having an increased activity and/or inducibility, were associated with a higher level of DNA adducts formation and an increased risk to certain types of carcinoma compared to the wild type (standard or non-mutated) allele [10,11]. On the other hand, individuals with a lower activation potential, related to the wild type allele(s) seem to be protected against cancer [12]. Several polymorphisms have been described in CYP2E1 [8,9,13,14].…”

La leucémie de l’enfant

“…Les de l'allèle sauvage disposent d'un plus faible potentiel d'activation des carcinogènes et semblent être protégés contre le cancer [10]. Plusieurs polymorphismes de CYP2E1 ont été décrits [8].…”