Abstract
Aristolochic acid (AA), a plant nephrotoxin and carcinogen, causes aristolochic acid nephropathy (AAN) and its associated urothelial malignancy, and is hypothesized to be responsible for Balkan endemic nephropathy (BEN). The major component of AA, aristolochic acid I (AAI), is the predominant compound responsible for these diseases. The reductive activation of AAI leads to the formation of covalent DNA adducts. The most abundant DNA adduct, 7-(deoxyadenosin-N6-yl)aristolactam I, causes characteristic AT→TA transversions found in the TP53 tumor suppressor gene in tumors from AAN and BEN patients. Understanding which human enzymes are involved in AAI activation to species forming DNA adducts and/or detoxication to the AAI O-demethylated metabolite, aristolochic acid Ia (AAIa), is important in the assessment of the susceptibility to this carcinogen. This review summarizes the latest data on identifying human and rodent enzymes participating in AAI metabolism. NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient cytosolic nitroreductase activating AAI in vitro and in vivo. In human hepatic microsomes, AAI is activated by cytochrome P450 1A2 (CYP1A2) and, to a lesser extent, by CYP1A1; NADPH:CYP oxidoreductase also plays a minor role. Human and rodent CYP1A1 and 1A2 are also the principal enzymes involved in oxidative detoxication of AAI to AAIa in vitro and in vivo. The orientation of AAI in the active sites of human CYP1A1/2 and NQO1 was predicted from molecular modeling and is consistent with the efficient reduction of AAI by them observed experimentally. Molecular modeling also shows why CYP1A2 plays an important role in the oxidation of AAI to AAIa.
Keywords: Aristolochic acid, aristolochic acid nephropathy, Balkan endemic nephropathy, metabolic activation and detoxication; biotransformation enzymes; NAD(P)H:quinone oxidoreductase, cytochromes P450 1A1 and 1A2.
Call for Papers in Thematic Issues
Interaction between drugs and endocrine diseases
The introduction of highly active antiretroviral therapy accelerated studies and our understanding on the interaction between pharmacological therapies and endocrine diseases. Drugs can precipitate endocrine via different mechanisms, including direct alteration of hormone production and secretion, dysregulation of hormonal axis, effects on hormonal transport, receptor-binding, and cellular signalling. Common drug-induced ...read more
Tissue Distribution and Metabolism of Micro- and Nanoparticles and Medical Implants
With the continuous advancement of modern science and engineering, numerous functional materials and active molecules have been developed and utilized in various industrial, medical, and food applications. Many of these can enter the body, either actively or passively, and have significant and intricate impacts on human health. For example, biomaterials ...read more
Related Books
Nanoparticles and Nanocarriers Based Pharmaceutical Formulations
Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part I
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part II
Mixed Polymeric Micelles for Osteosarcoma Therapy: Development and Characterization
A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems
Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part II)
Nanomaterials: Evolution and Advancement Towards Therapeutic Drug Delivery (Part I)
67