Biomaterial Database

Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. 1995

G Jönsson, and A Aström, and P Andersson

Astra Draco AB, Kinetics and Metabolism, Lund, Sweden.

Budesonide is a synthetic glucocorticosteroid that is commonly used in topical treatment of asthma and rhinitis. The main metabolites formed from budesonide in human liver microsomes have been identified as 16 alpha-hydroxyprednisolone and 6 beta-hydroxy-budesonide. Although it is apparent that the cytochrome P450 (CYP) system is involved, the actual subfamily has not been identified. In attempts to do this, budesonide was incubated with microsomes from ten different human liver samples where various CYP activities had been rank ordered. We found a strong correlation between formation of the two main metabolites and testosterone 6 beta-hydroxylation (correlation 0.98 and 0.95), a marker for CYP3A. When budesonide (10 microM) was incubated with human liver microsomes in the presence of compounds known to interact with different isoforms or subfamilies of CYP, ketoconazole was found to be the strongest inhibitor of budesonide metabolism (IC50: approximately 0.1 microM) followed by troleandomycin (IC50: approximately 1 microM), erythromycin, and cyclosporin, all substances known to interact with CYP3A isoenzymes. Substances known to interact with CYP2C (sulfaphenazole, mephenytoin, and tolbutamide) and with CYP2D6 (bufuralol and quinidine) did not specifically inhibit the metabolism of budesonide. In addition, formation of the budesonide metabolites (16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide) was inhibited by antibodies against the CYP3A subfamily, but not by antibodies against the CYP1A subfamily or control immunoglobulin G. We conclude that the formation of 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide from budesonide is catalyzed by isoenzymes within the CYP3A subfamily.

UI	MeSH Term	Description	Entries
D007074	Immunoglobulin G	The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B.	Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D007527	Isoenzymes	Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.	Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D008297	Male		Males
D008862	Microsomes, Liver	Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.	Liver Microsomes,Liver Microsome,Microsome, Liver
D008875	Middle Aged	An adult aged 45 - 64 years.	Middle Age
D011239	Prednisolone	A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states.	Di-Adreson-F,Predate,Predonine,Di Adreson F,DiAdresonF
D011282	Pregnenediones	Unsaturated pregnane derivatives containing two keto groups on side chains or ring structures.	Diketopregnenes,Dioxopregnenes
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D005260	Female		Females
D005938	Glucocorticoids	A group of CORTICOSTEROIDS that affect carbohydrate metabolism (GLUCONEOGENESIS, liver glycogen deposition, elevation of BLOOD SUGAR), inhibit ADRENOCORTICOTROPIC HORMONE secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system.	Glucocorticoid,Glucocorticoid Effect,Glucorticoid Effects,Effect, Glucocorticoid,Effects, Glucorticoid