Acetylation as an Indicator of Risk

Abstract

Aromatic amine acetylation has been recognized for many years as an important metabolic polymorphism in humans because of its relationship to disease. This system serves as a model in risk assessment because of its role in drug and carcinogen activation and detoxification and because of the ease with which it is measured. However, possible interactions of NAT1-NAT2 phenotypes or genotypes illustrate the complexity of xenobiotic metabolism pathways. Moreover, the use of such information for risk assessment is further complicated by the association of the rapid phenotype with increased risk in colon cancer and the slow phenotype with increased risk in urinary bladder cancer. Before this biomarker can be effectively utilized as a significant predictor of individual risk, it will be necessary to identify specific sources of aromatic amine exposure and to characterize further the substrate specificity of NAT1 and NAT2 in relation to the multiplicity of enzyme variants occurring in human populations. Environ Health Perspect 105(Suppl 4): 763-766 (1997)

Metabolism by N‐Acetyltransferase 1 In Vitro and in Healthy Volunteers: A Prototype for Targeted Inhibition

“…13 As an extension of this category, even in the absence of drug therapy, there have been several linkages reported between acetylation rates and predisposition to diseases as diverse as cancers and lupus. 3,4 In certain situations, individuals with a rapid acetylation pheno- 3 41 Male Caucasian 4 41 Female Caucasian 5 29 Male Caucasian 6 44 Female African American type have a 10-fold or greater risk of disease than individuals with a slow acetylation phenotype. For these situations, it is a reasonable hypothesis that inhibition of NAT could be beneficial to patients.…”

“…As an extension of this category, even in the absence of drug therapy, there have been several linkages reported between acetylation rates and predisposition to diseases as diverse as cancers and lupus 3,4 . In certain situations, individuals with a rapid acetylation phenotype have a 10‐fold or greater risk of disease than individuals with a slow acetylation phenotype.…”

“…strates into more toxic species, including carcinogens. 4,5 Clearance of parent compounds is reduced and their respective concentrations are higher in slow metabolizers compared to rapid metabolizers. As a result, slow metabolizers are generally more prone to those adverse drug reactions linked to parent drug concentrations.…”

“…On one side, conjugation via NAT plays an important role in drug detoxification and elimination from the body. On the other side, it can convert substrates into more toxic species, including carcinogens 4,5 . Clearance of parent compounds is reduced and their respective concentrations are higher in slow metabolizers compared to rapid metabolizers.…”

Biologische Marker in der Epidemiologie: Begriffe, Anwendungen, Perspektiven (Teil II)

“…Während beispielsweise das Vorliegen zweier intakter Allele des GSTM1-Gens (phänotypisch hohe Aktivität des Enzyms) das Lungenkrebsrisiko durch Zigarettenrauchen und möglicherweise auch das Blasenkrebsrisiko vermindert [28], werden andererseits Haloalkane und -alkene aktiviert, woraus wiederum ein erhöhtes Risiko für Magen-, Darm-oder Leberkrebs resultiert [29]. Schnelle Acetylierer haben nicht nur ein vermindertes Blasenkrebsrisiko bei Belastung durch Arylamine [20,27,30], sondern gleichzeitig ein erhöhtes Risiko für Dickdarmkrebs und möglicherweise auch für Brustkrebs [30].…”