S29 Aldehyde oxidases, a family of emerging interest in xenobiotic and drug metabolism: structural and functional studies

Enrico Garattini , IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Title: Aldehyde oxidases, a family of emerging interest in xenobiotic and drug metabolism: structural and functional studies.

Enrico Garattini, Head of the Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, via La Masa 19, 20156 Milano, Italy. E-mail: enrico.garattini@marionegri.it

Mammalian aldehyde oxidases (AOXs) are a family of enzymes characterized by broad substrate specificity, as they oxidize aliphatic and aromatic aldehydes and hydroxylate numerous heterocycles. AOXs are cytosolic proteins which play an ever increasing role in the metabolism of different types of drugs and xenobiotics. The human genome is characterized by the presence of a single and functionally active AOX gene, i.e. AOX1, while the genome of rats and mice is characterized by four distinct genes coding for an equivalent number of proteins (AOX1, AOX2, AOX3 and AOX4) This difference is of particular importance in the context of drug-metabolism and drug-development studies. In fact, mice and rats are unlikely to represent predictive experimental models to perform pre-clinical studies aimed at defining the pharmacokinetics and pharmacodynamics of novel drugs which act as human AOX1 substrates. Besides, their significance for drug metabolism, AOXs are also implicated in other physiological function. A series of recent studies conducted by our group indicate that AOXs are involved in the control of fat deposition, which make them potential targets for the development of anti-obesity agents. The main objective of the presentation is to provide aan updated summary of the knowledge available on the structure and function of mammalian aldehyde oxidases, with particular reference on the role played by this family of enzymes in drug-metabolism and drug-development.