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Identification of the Xenobiotic-Metabolizing Enzyme Arylamine N-Acetyltransferase 1 as a New Target of Cisplatin in Breast Cancer Cells: Molecular and Cellular Mechanisms of Inhibition

Laboratoire de Cytophysiologie et Toxicologie Cellulaire (EA 1553) (N.R., J.D., B.P., M.M., E.P., J.-M.D., F.R.-L.), Unitéde Formation et de Recherche des Sciences du Vivant (J.D., N.J., J.-M.D., F.R.-L.), and Modèles de Dérégulation Génique: Trisomie 21 et Hyperhomocystéinémie (EA 3508) (N.J.), Université Paris Diderot-Paris 7, Paris, France

Arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic-metabolizing enzyme that plays an important role in the biotransformation of aromatic drugs and carcinogens. NAT1 activity has long been associated with susceptibility to various cancers. Evidence for a role of NAT1 in malignant progression has also been obtained, particularly for breast and prostate cancer. Cisplatin is widely used in chemotherapy against human cancers, and it is thought to act principally by forming DNA adducts. However, recent studies have suggested that some of the pharmacological and/or toxicological effects of cisplatin may be due to the direct targeting and inhibition of certain cellular enzymes. We show here that the exposure of breast cancer cells, known to express functional NAT1 enzyme, to therapeutically relevant concentrations of cisplatin impairs the catalytic activity of endogenous NAT1. Endogenous NAT1 was also found to be inactivated, in vivo, in the tissues of mice treated with cisplatin. Mechanistic studies with purified human NAT1 indicated that this inhibition resulted from the irreversible formation of a cisplatin adduct with the active-site cysteine residue of the enzyme. Kinetic studies suggested that NAT1 interacts rapidly with cisplatin, with a second-order rate inhibition constant of 700 M^-1 min^-1. This rate constant is one the highest ever reported for the reaction of cisplatin with a biological macromolecule. Few enzymes have been clearly shown to be inactivated by cisplatin. We provide here molecular and cellular evidence suggesting that NAT1 is one of the targets of cisplatin in cells.

Address correspondence to: Dr. Fernando Rodrigues-Lima, Laboratoire de Cytophysiologie et Toxicologie Cellulaire (EA 1553), Université Paris Diderot-Paris 7, 75005, Paris, France. E-mail: fernando.rodrigues-lima{at}univ-paris-diderot.fr