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Multidrug resistance associated protein ATP-binding cassette sub-family C member 3 Cytochrome P450 3A4 Cytochrome P450 3A5 UDP- glucuronosyltransferase 1-9 UDP- glucuronosyltransferase 2B7 Dihydroartemisinin (DHA) Heme Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Artesunate Artesunate Superoxide Hydroxyl Radical Uridine diphosphate glucuronic acid Dihydroartemisinin glucuronide Uridine 5'-diphosphate NADH O2 Formaldehyde NAD H2O Heme Heme Endoplasmic Reticulum Hepatocyte Artesunate is readily absorbed into the body and goes through first pass metabolism. Artemether is then broken down within the hepatocyte by cytochrome P450 into its active metabolite dihydroartemisinin (DHA). DHA is then further broken down into dihydroartemisinin glucuronide by UDP-glucuronosyltransferase. This now becomes an inactive metabolite that is then eliminated from the body by excretion of bile. DHA interacts with the heme in the parasitic food vacoule causing the production of radical species that inhibit protein and nucleic acid synthesis, causing damage and eventually death. Malaria Cell Cytosol Vacuole Erythrocyte Blood Vessel Liver
Melanosome Vacuole Endoplasmic Reticulum MRP3 ABCC3 CYP3A4 CYP3A5 UGT1A9 UGT2B7 Dihydroartemisinin (DHA) Heme Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Dihydroartemisinin (DHA) Artesunate Artesunate Superoxide Hydroxyl Radical Uridine diphosphate glucuronic acid Dihydroartemisinin glucuronide Uridine 5'-diphosphate NADH Oxygen Formaldehyde NAD Water
MRP3 ABCC3 CYP3A4 CYP3A5 UGT1A9 UGT2B7 DHAMN Heme DHAMN DHAMN DHAMN DHAMN Artes Artes O2(-) Hyd Rad UDPGlcA Alaxin UDP NADH O2 Formol NAD H