DOXORUBICIN PHARMACOKINETICS PATHWAY (PW:0001565)
Description Doxorubucin (DOX, trade name Adriamycin) is an anthracycline derived from Streptomyces bacterium Streptomyces peucetius var. caesius . DOX is used in the treatment of several solid cancers, leukemia and lymphomas. The drug is composed of a planar aromatic ring with an anthraquinone chromophore and a sugar group. Once taken up by the cell and inside the nucleus for which it has a high affinity, the planar ring structure intercalates between adjacent DNA base pairs, preferentially GC base pairs. DOX can form DNA adducts, binds to DNA and topoisomerases and inhibits DNA replication and transcription. It promotes DNA double-strand breaks (DSBs) and the DNA damage prompts various responses, including cell cycle arrest and apoptosis, primarily via activation of p53 pathway but also independent of it, with beneficial, if tumor cells, or otherwise detrimental consequences. While toxic to the tumor cell, DOX is also toxic to all other cell types. The cardiotoxicity of the drug is the main and the most severe adverse effect, and the cardiomyopathies associated with DOX can eventually lead to heart failure. The formation of reactive oxygen species (ROS), impaired iron homeostasis and mitochondrial dysfunction are thought to underlie the cardiotoxicity of DOX. Although more than 50% of DOX is eliminated unchanged, the drug undergoes several types of transformation such as two- and one-electron reduction and to a smaller extent deglycosidation. Free radical generation is a feature of DOX metabolism. The drug can interact with iron and generate hydroxyl radical and with the iron-responsive elements (IRE) regions of mRNAs, it can impact on the function of iron regulatory proteins (IRPs) and disturb iron homeostasis. In addition, DOX localizes to mitochondria, forms adducts with mitochondrial DNA, interacts with cardiolipin - an essential component of inner mitochondrial membrane, and is capable of impacting on a number of proteins/enzymes important for mitochondrial function. Doxorubicin is also administered as a pegylated liposomal product.
The uptake of DOX is mediated by Slc22a16, while several transporters are involved in the elimination of the drug. Those include Abcb1, Abcc2 and Abcc3, Abcg2 and Ralbp1. As mentioned, there are several routes of DOX processing. The most common one is the two-electron reduction, followed by the one-electron reduction. The Cbr1 and Cbr3, and the Akr1a1 and Akr1c3 carry out the two-electron reduction. Xdh and Nqo1 and the endothelial nitric oxide synthase Nos3, carry out the one-electron reduction. The deglycosidation of DOX accounts for only ~1-2% of processing and the enzymes involved are still to be characterized. Both the one-electron and the deglycosidation reactions generate ROS. In the one-electron reduction the quinone moiety generates a semiquinone radical that regenerates the parent quinone by reducing molecular oxygen to ROS. It is believed that further processing of metabolites via glucuronidation, sulfation or methylation is necessary before they can be eliminated. To see the ontology report for annotations, GViewer and download, click here
...(less)
Pathway Diagram:
Genes in Pathway:
G
Abcb1a ATP binding cassette subfamily B member 1A
4
22,339,829
22,517,642
RGD:10395261 RGD:10402751
G
Abcc1 ATP binding cassette subfamily C member 1
10
549,537
672,235
RGD:10402751
G
Abcc2 ATP binding cassette subfamily C member 2
1
263,554,426
263,612,556
RGD:10395261 RGD:10402751
G
Abcc3 ATP binding cassette subfamily C member 3
10
82,047,308
82,116,928
RGD:10395261
G
Abcg2 ATP binding cassette subfamily G member 2
4
88,765,441
88,890,268
RGD:10395261 RGD:10402751
G
Akr1a1 aldo-keto reductase family 1 member A1
5
135,482,068
135,498,693
RGD:10395261 RGD:10402751 RGD:10395262
G
Akr1c3 aldo-keto reductase family 1, member C3
17
69,761,126
69,778,021
RGD:10395261 RGD:10402751
G
Cbr1 carbonyl reductase 1
11
33,813,041
33,815,418
RGD:10395261 RGD:10402751 RGD:10395262
G
Cbr3 carbonyl reductase 3
11
33,909,417
33,917,674
RGD:10395261 RGD:10402751 RGD:10395262
G
Ndufs2 NADH:ubiquinone oxidoreductase core subunit S2
13
89,606,848
89,623,506
RGD:10402751
G
Ndufs3 NADH:ubiquinone oxidoreductase core subunit S3
3
79,721,686
79,728,863
RGD:10402751
G
Ndufs7 NADH:ubiquinone oxidoreductase core subunit S7
7
12,318,776
12,326,403
RGD:10402751
G
Nos3 nitric oxide synthase 3
4
7,321,908
7,342,404
RGD:10395262 RGD:10402751
G
Nqo1 NAD(P)H quinone dehydrogenase 1
19
38,422,210
38,437,103
RGD:10395262 RGD:10402751
G
Por cytochrome p450 oxidoreductase
12
23,998,411
24,017,063
RGD:10402751
G
Ralbp1 ralA binding protein 1
9
113,579,107
113,598,477
RGD:10395261 RGD:10402751
G
Slc22a16 solute carrier family 22 member 16
20
45,658,398
45,669,192
RGD:10395261 RGD:10402751
G
Xdh xanthine dehydrogenase
6
25,149,570
25,211,273
RGD:10395262 RGD:10402751
Pathway Gene Annotations
Disease Annotations Associated with Genes in the doxorubicin pharmacokinetics pathway
Abcb1a adrenocortical carcinoma , allergic rhinitis , Alzheimer's disease , Anthracycline-induced Cardiotoxicity , asthma , autosomal recessive limb-girdle muscular dystrophy type 2B , autosomal recessive limb-girdle muscular dystrophy type 2J , Behcet's disease , Breast Neoplasms , cannabis abuse , carcinoma , Chemical and Drug Induced Liver Injury , chronic myeloid leukemia , Colorectal Neoplasms , congenital heart disease , Crohn's disease , Cronkhite-Canada syndrome , Diabetes Mellitus, Experimental , diffuse large B-cell lymphoma , disease of cellular proliferation , disease of mental health , Disease Progression , Drug-induced Neutropenia , Drug-Related Side Effects and Adverse Reactions , encephalitis , end stage renal failure , Endotoxemia , Eosinophilia , epilepsy , Escherichia Coli Infections , Esophageal Neoplasms , Experimental Arthritis , Experimental Liver Cirrhosis , familial hyperlipidemia , familial temporal lobe epilepsy 3 , Fetal Growth Retardation , Genetic Predisposition to Disease , Germ Cell and Embryonal Neoplasms , heart disease , Hematologic Neoplasms , hepatocellular carcinoma , human immunodeficiency virus infectious disease , Hypotension, Orthostatic , Inflammation , inflammatory bowel disease 13 , invasive ductal carcinoma , kidney disease , Kidney Neoplasms , Lymphoma, Extranodal NK-T-Cell , Mammary Neoplasms, Experimental , Nasal Polyps , Nausea , Neoplasm Metastasis , nephroblastoma , nervous system disease , neuroblastoma , neutropenia , non-small cell lung carcinoma , nonalcoholic fatty liver disease , obstructive sleep apnea , Ovarian Neoplasms , Pain , Pain, Postoperative , Parkinson's disease , perinatal necrotizing enterocolitis , peripheral nervous system disease , pleomorphic xanthoastrocytoma , Poisoning , precursor lymphoblastic lymphoma/leukemia , renal cell carcinoma , Reperfusion Injury , rheumatoid arthritis , secondary Parkinson disease , status epilepticus , temporal lobe epilepsy , toxic encephalopathy , Translocation, Genetic , type 2 diabetes mellitus , visual epilepsy , Vomiting Abcc1 Alzheimer's disease , asthma , bacterial pneumonia , Breast Cancer, Familial , Breast Neoplasms , Chemical and Drug Induced Liver Injury , chronic obstructive pulmonary disease , Colorectal Neoplasms , Disease Progression , Drug-Related Side Effects and Adverse Reactions , heart disease , hypertension , peripheral nervous system disease , pseudoxanthoma elasticum , schizophrenia Abcc2 Acute Liver Failure , alopecia , bilirubin metabolic disorder , Chemical and Drug Induced Liver Injury , cholangiocarcinoma , cholestasis , chronic myeloid leukemia , Colorectal Neoplasms , Diabetes Mellitus, Experimental , drug allergy , Drug-Induced Immune Thrombocytopenia , Drug-induced Neutropenia , Drug-Related Side Effects and Adverse Reactions , Dubin-Johnson syndrome , end stage renal failure , Endotoxemia , Experimental Liver Cirrhosis , fatty liver disease , Gastrointestinal Diseases , heart disease , nervous system disease , non-small cell lung carcinoma , nonalcoholic fatty liver disease , pancreatic cancer , precursor lymphoblastic lymphoma/leukemia , primary biliary cirrhosis , rheumatoid arthritis , status epilepticus , type 2 diabetes mellitus , visual epilepsy Abcc3 acute myeloid leukemia , bilirubin metabolic disorder , cholestasis , Colorectal Neoplasms , Diabetes Mellitus, Experimental , Dubin-Johnson syndrome , end stage renal failure , fatty liver disease , hepatocellular carcinoma , Hepatomegaly , hyperprolactinemia , kidney disease , nonalcoholic fatty liver disease , pancreatic cancer , rheumatoid arthritis , Smith-Magenis syndrome Abcg2 acute myeloid leukemia , adenoma , B-Cell Chronic Lymphocytic Leukemia , B-cell lymphoma , Breast Neoplasms , chronic myeloid leukemia , Colorectal Neoplasms , diabetes mellitus , Diabetes Mellitus, Experimental , diffuse large B-cell lymphoma , Drug-Related Side Effects and Adverse Reactions , erythropoietic protoporphyria , Experimental Arthritis , gout , hyperuricemia , Liver Injury , Mammary Neoplasms, Experimental , megakaryocytic leukemia , multiple myeloma , nervous system disease , Ovarian Neoplasms , precursor lymphoblastic lymphoma/leukemia , precursor T-lymphoblastic lymphoma/leukemia , primary biliary cirrhosis , renal cell carcinoma , Reperfusion Injury , rheumatoid arthritis , secondary hyperparathyroidism , status epilepticus , toxic encephalopathy Akr1a1 Charcot-Marie-Tooth disease dominant intermediate C , perinatal necrotizing enterocolitis Akr1c3 Castration-Resistant Prostatic Neoplasms , Cell Transformation, Neoplastic , ductal carcinoma in situ , Endometrial Neoplasms , endometriosis , Experimental Liver Cirrhosis , leukemia , myeloid neoplasm , Neoplasms, Hormone-Dependent , obesity , polycystic ovary syndrome , pre-eclampsia , precursor B lymphoblastic lymphoma/leukemia , precursor T-lymphoblastic lymphoma/leukemia , prostate cancer , Prostatic Neoplasms , sex differentiation disease , Stomach Neoplasms Cbr1 cardiomyopathy , chronic kidney disease , Colonic Neoplasms , Diabetes Mellitus, Experimental , end stage renal failure , Fever , hepatocellular carcinoma , irritant dermatitis , Prostatic Neoplasms Cbr3 Mouth Neoplasms Ndufs2 cardiomyopathy , Diabetes Mellitus, Experimental , hypertrophic cardiomyopathy , inherited metabolic disorder , Leber hereditary optic neuropathy , Leigh disease , mitochondrial complex I deficiency , mitochondrial encephalomyopathy , multiple sclerosis Ndufs3 Alzheimer's disease , Breast Neoplasms , Cardiomegaly , Chemical and Drug Induced Liver Injury , Diabetes Mellitus, Experimental , Diabetic Nephropathies , genetic disease , Leigh disease , Leigh Syndrome Due To Mitochondrial Complex I Deficiency , mitochondrial complex I deficiency , optic atrophy , Parkinsonian Disorders Ndufs7 bipolar disorder , guanidinoacetate methyltransferase deficiency , Leigh disease , Leigh Syndrome Due To Mitochondrial Complex I Deficiency , mitochondrial complex I deficiency Nos3 acute chest syndrome , acute kidney failure , Acute Liver Failure , acute myeloid leukemia , adenocarcinoma , Alzheimer's disease , Alzheimer's disease 1 , angle-closure glaucoma , anterior ischemic optic neuropathy , aortic valve disease , arteriosclerosis , Arteriovenous Fistula , asthma , atherosclerosis , atrial fibrillation , Behcet's disease , bladder neck obstruction , Brain Hypoxia , brain ischemia , Breast Neoplasms , Bronchial Hyperreactivity , bronchiolitis obliterans , Cardiomegaly , cardiomyopathy , Cardiotoxicity , cardiovascular system disease , Carotid Artery Injuries , central sleep apnea , cerebral infarction , Child Behavior Disorders , cholestasis , Chronic Cerebral Hypoperfusion , chronic kidney disease , chronic obstructive pulmonary disease , cleft lip , cleft palate , colitis , congenital diaphragmatic hernia , congestive heart failure , coronary artery disease , coronary artery vasospasm , cystic fibrosis , Diabetes Mellitus, Experimental , diabetic angiopathy , Diabetic Cardiomyopathies , Diabetic Gastroparesis , Diabetic Nephropathies , diabetic retinopathy , Diaphragmatic Hernia , disease of cellular proliferation , Drug-Induced Enteropathy , end stage renal failure , Endometrial Neoplasms , Endotoxemia , Esophageal Neoplasms , essential hypertension , Experimental Arthritis , Experimental Liver Cirrhosis , extrahepatic cholestasis , familial hyperlipidemia , Fetal Growth Retardation , gastric ulcer , Graft Occlusion, Vascular , Hearing Loss, Sudden , Hepatic Insufficiency , Hepatomegaly , hepatopulmonary syndrome , Huntington's disease , Hyperemia , hyperglycemia , hyperinsulinism , Hyperoxia , hypertension , Hypertension Resistant to Conventional Therapy , Hypertension, Pregnancy-Induced , Hypertriglyceridemia , hypothyroidism , Hypoxia , impotence , Insulin Resistance , intestinal perforation , Intestinal Reperfusion Injury , Intimal Hyperplasia , intracranial aneurysm , Intracranial Hemorrhages , irritable bowel syndrome , ischemia , Kidney Reperfusion Injury , Kuhnt-Junius degeneration , Left Ventricular Hypertrophy , leiomyoma , Limb Ischemia , liver cirrhosis , Liver Reperfusion Injury , long QT syndrome , lung disease , Lung Reperfusion Injury , lymphangioleiomyomatosis , Lymphatic Metastasis , macular retinal edema , male infertility , malignant glioma , Metabolic Syndrome , migraine , myocardial infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , Nasal Polyps , Neoplasm Metastasis , nephritis , obesity , obstructive sleep apnea , Ovarian Neoplasms , overnutrition , Pain , Perennial Allergic Rhinitis , perinatal necrotizing enterocolitis , persistent fetal circulation syndrome , Phyllodes Tumor , placental abruption , polycystic kidney disease , portal hypertension , pre-eclampsia , precursor lymphoblastic lymphoma/leukemia , primary biliary cirrhosis , primary open angle glaucoma , Prostatic Neoplasms , pulmonary edema , pulmonary embolism , pulmonary emphysema , pulmonary eosinophilia , pulmonary hypertension , Pulmonary Hypertension, Hypoxia-Induced , Radiation Pneumonitis , renal hypertension , renovascular hypertension , Reperfusion Injury , respiratory allergy , Retina Reperfusion Injury , retinal degeneration , retinopathy of prematurity , Right Ventricular Hypertrophy , Sepsis , Shock, Hemorrhagic , sickle cell anemia , Spinal Cord Compression , Spinal Cord Injuries , Stomach Neoplasms , Stroke , Subarachnoid Hemorrhage , telangiectasis , Testis Reperfusion Injury , Thromboembolism , Thrombotic Microangiopathies , transient cerebral ischemia , Transplant Rejection , type 1 diabetes mellitus , type 2 diabetes mellitus , uremia , ureteral obstruction , urinary bladder cancer , vasculitis , Vaso-occlusive Crisis , Venous Thrombosis , Ventricular Dysfunction, Right , Ventricular Premature Complexes , Ventricular Tachycardia , vestibular disease , Vulvar Neoplasms Nqo1 acute kidney failure , Acute Lung Injury , acute myeloid leukemia , asthma , Brain Injuries , breast cancer , Breast Neoplasms , Carbon Tetrachloride Poisoning , Cerebral Hemorrhage , Chemical and Drug Induced Liver Injury , cholestasis , Chromosome 8, Trisomy , chronic kidney disease , chronic myeloid leukemia , chronic obstructive pulmonary disease , Colonic Neoplasms , Colorectal Neoplasms , contact dermatitis , Diabetes Mellitus, Experimental , Diabetic Nephropathies , disease of cellular proliferation , Experimental Arthritis , Experimental Liver Neoplasms , Experimental Neoplasms , fatty liver disease , hemolytic-uremic syndrome , Hemorrhage , hyperglycemia , Hyperoxia , Hyperoxic Lung Injury , hypertension , Intestinal Reperfusion Injury , kidney disease , Kidney Reperfusion Injury , Lead Poisoning , Left Ventricular Hypertrophy , leukemia , liver benign neoplasm , liver cirrhosis , liver disease , lung cancer , lung disease , Lung Injury , Lung Neoplasms , Lung Reperfusion Injury , macular degeneration , membranous glomerulonephritis , mental depression , Mercury Poisoning , middle cerebral artery infarction , multiple myeloma , myelodysplastic syndrome , myeloid leukemia , myeloid neoplasm , neurodegenerative disease , non-small cell lung carcinoma , nonalcoholic fatty liver disease , obesity , Occupational Diseases , Overactive Urinary Bladder , Pancreatitis, Experimental, Chronic , papilloma , Parkinson's disease , Poisoning , precursor lymphoblastic lymphoma/leukemia , Prostatic Neoplasms , prostatitis , pulmonary emphysema , renal fibrosis , small cell carcinoma , Spinal Cord Injuries , spinocerebellar ataxia type 17 , status epilepticus , Subarachnoid Hemorrhage , toxic encephalopathy , transient cerebral ischemia , ureteral obstruction , urinary bladder cancer , Urologic Neoplasms , visual epilepsy , Warfarin Sensitivity Por amenorrhea , Antley-Bixler syndrome , Antley-Bixler Syndrome with Genital Anomalies and Disordered Steroidogenesis , ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS , Cell Transformation, Neoplastic , congenital adrenal hyperplasia , gliosarcoma , Hypotension , learning disability , Musculoskeletal Abnormalities , neural tube defect , pleomorphic xanthoastrocytoma , urinary bladder cancer Ralbp1 hypertension , microphthalmia , Myocardial Ischemia , Prostatic Neoplasms , urinary bladder cancer Slc22a16 juvenile rheumatoid arthritis Xdh acute kidney failure , Acute Lung Injury , Animal Mammary Neoplasms , Arterial Thrombosis , autistic disorder , Brain Injuries , Carbon Monoxide Poisoning , carcinoma , cardiomyopathy , cardiovascular system disease , carotid artery disease , cataract , cholestasis , chronic kidney disease , Colonic Neoplasms , congestive heart failure , Diabetes Mellitus, Experimental , Diabetic Cardiomyopathies , Diabetic Nephropathies , Experimental Arthritis , Experimental Liver Neoplasms , gout , heart disease , hepatocellular carcinoma , Hyperoxaluria , Hyperoxic Lung Injury , hypertension , hyperuricemia , Hypotension , interstitial nephritis , Intestinal Reperfusion Injury , ischemia , kidney failure , Kidney Reperfusion Injury , Left Ventricular Hypertrophy , Lesch-Nyhan syndrome , Liver Reperfusion Injury , major depressive disorder , Mammary Neoplasms, Experimental , middle cerebral artery infarction , Multiple Organ Failure , muscular disease , Myocardial Reperfusion Injury , Nephrosis, Puromycin Aminonucleoside , Nerve Degeneration , obesity , pancreatitis , peritonitis , Pneumoperitoneum , portal hypertension , protein-losing enteropathy , pulmonary embolism , renal fibrosis , Renal Ischemia , Reperfusion Injury , Retina Reperfusion Injury , Sepsis , Shock , Spinal Cord Injuries , Testis Reperfusion Injury , thrombocytopenia , Transplant Rejection , urinary bladder cancer , Wounds, Penetrating , xanthinuria , Xanthinuria, Type I , Xanthinuria, Type II
acute chest syndrome Nos3 acute kidney failure Nos3 , Nqo1 , Xdh Acute Liver Failure Abcc2 , Nos3 Acute Lung Injury Nqo1 , Xdh acute myeloid leukemia Abcc3 , Abcg2 , Nos3 , Nqo1 adenocarcinoma Nos3 adenoma Abcg2 adrenocortical carcinoma Abcb1a allergic rhinitis Abcb1a alopecia Abcc2 Alzheimer's disease Abcb1a , Abcc1 , Ndufs3 , Nos3 Alzheimer's disease 1 Nos3 amenorrhea Por angle-closure glaucoma Nos3 Animal Mammary Neoplasms Xdh anterior ischemic optic neuropathy Nos3 Anthracycline-induced Cardiotoxicity Abcb1a Antley-Bixler syndrome Por Antley-Bixler Syndrome with Genital Anomalies and Disordered Steroidogenesis Por ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS Por aortic valve disease Nos3 Arterial Thrombosis Xdh arteriosclerosis Nos3 Arteriovenous Fistula Nos3 asthma Abcb1a , Abcc1 , Nos3 , Nqo1 atherosclerosis Nos3 atrial fibrillation Nos3 autistic disorder Xdh autosomal recessive limb-girdle muscular dystrophy type 2B Abcb1a autosomal recessive limb-girdle muscular dystrophy type 2J Abcb1a B-Cell Chronic Lymphocytic Leukemia Abcg2 B-cell lymphoma Abcg2 bacterial pneumonia Abcc1 Behcet's disease Abcb1a , Nos3 bilirubin metabolic disorder Abcc2 , Abcc3 bipolar disorder Ndufs7 bladder neck obstruction Nos3 Brain Hypoxia Nos3 Brain Injuries Nqo1 , Xdh brain ischemia Nos3 breast cancer Nqo1 Breast Cancer, Familial Abcc1 Breast Neoplasms Abcb1a , Abcc1 , Abcg2 , Ndufs3 , Nos3 , Nqo1 Bronchial Hyperreactivity Nos3 bronchiolitis obliterans Nos3 cannabis abuse Abcb1a Carbon Monoxide Poisoning Xdh Carbon Tetrachloride Poisoning Nqo1 carcinoma Abcb1a , Xdh Cardiomegaly Ndufs3 , Nos3 cardiomyopathy Cbr1 , Ndufs2 , Nos3 , Xdh Cardiotoxicity Nos3 cardiovascular system disease Nos3 , Xdh carotid artery disease Xdh Carotid Artery Injuries Nos3 Castration-Resistant Prostatic Neoplasms Akr1c3 cataract Xdh Cell Transformation, Neoplastic Akr1c3 , Por central sleep apnea Nos3 Cerebral Hemorrhage Nqo1 cerebral infarction Nos3 Charcot-Marie-Tooth disease dominant intermediate C Akr1a1 Chemical and Drug Induced Liver Injury Abcb1a , Abcc1 , Abcc2 , Ndufs3 , Nqo1 Child Behavior Disorders Nos3 cholangiocarcinoma Abcc2 cholestasis Abcc2 , Abcc3 , Nos3 , Nqo1 , Xdh Chromosome 8, Trisomy Nqo1 Chronic Cerebral Hypoperfusion Nos3 chronic kidney disease Cbr1 , Nos3 , Nqo1 , Xdh chronic myeloid leukemia Abcb1a , Abcc2 , Abcg2 , Nqo1 chronic obstructive pulmonary disease Abcc1 , Nos3 , Nqo1 cleft lip Nos3 cleft palate Nos3 colitis Nos3 Colonic Neoplasms Cbr1 , Nqo1 , Xdh Colorectal Neoplasms Abcb1a , Abcc1 , Abcc2 , Abcc3 , Abcg2 , Nqo1 congenital adrenal hyperplasia Por congenital diaphragmatic hernia Nos3 congenital heart disease Abcb1a congestive heart failure Nos3 , Xdh contact dermatitis Nqo1 coronary artery disease Nos3 coronary artery vasospasm Nos3 Crohn's disease Abcb1a Cronkhite-Canada syndrome Abcb1a cystic fibrosis Nos3 diabetes mellitus Abcg2 Diabetes Mellitus, Experimental Abcb1a , Abcc2 , Abcc3 , Abcg2 , Cbr1 , Ndufs2 , Ndufs3 , Nos3 , Nqo1 , Xdh diabetic angiopathy Nos3 Diabetic Cardiomyopathies Nos3 , Xdh Diabetic Gastroparesis Nos3 Diabetic Nephropathies Ndufs3 , Nos3 , Nqo1 , Xdh diabetic retinopathy Nos3 Diaphragmatic Hernia Nos3 diffuse large B-cell lymphoma Abcb1a , Abcg2 disease of cellular proliferation Abcb1a , Nos3 , Nqo1 disease of mental health Abcb1a Disease Progression Abcb1a , Abcc1 drug allergy Abcc2 Drug-Induced Enteropathy Nos3 Drug-Induced Immune Thrombocytopenia Abcc2 Drug-induced Neutropenia Abcb1a , Abcc2 Drug-Related Side Effects and Adverse Reactions Abcb1a , Abcc1 , Abcc2 , Abcg2 Dubin-Johnson syndrome Abcc2 , Abcc3 ductal carcinoma in situ Akr1c3 encephalitis Abcb1a end stage renal failure Abcb1a , Abcc2 , Abcc3 , Cbr1 , Nos3 Endometrial Neoplasms Akr1c3 , Nos3 endometriosis Akr1c3 Endotoxemia Abcb1a , Abcc2 , Nos3 Eosinophilia Abcb1a epilepsy Abcb1a erythropoietic protoporphyria Abcg2 Escherichia Coli Infections Abcb1a Esophageal Neoplasms Abcb1a , Nos3 essential hypertension Nos3 Experimental Arthritis Abcb1a , Abcg2 , Nos3 , Nqo1 , Xdh Experimental Liver Cirrhosis Abcb1a , Abcc2 , Akr1c3 , Nos3 Experimental Liver Neoplasms Nqo1 , Xdh Experimental Neoplasms Nqo1 extrahepatic cholestasis Nos3 familial hyperlipidemia Abcb1a , Nos3 familial temporal lobe epilepsy 3 Abcb1a fatty liver disease Abcc2 , Abcc3 , Nqo1 Fetal Growth Retardation Abcb1a , Nos3 Fever Cbr1 gastric ulcer Nos3 Gastrointestinal Diseases Abcc2 genetic disease Ndufs3 Genetic Predisposition to Disease Abcb1a Germ Cell and Embryonal Neoplasms Abcb1a gliosarcoma Por gout Abcg2 , Xdh Graft Occlusion, Vascular Nos3 guanidinoacetate methyltransferase deficiency Ndufs7 Hearing Loss, Sudden Nos3 heart disease Abcb1a , Abcc1 , Abcc2 , Xdh Hematologic Neoplasms Abcb1a hemolytic-uremic syndrome Nqo1 Hemorrhage Nqo1 Hepatic Insufficiency Nos3 hepatocellular carcinoma Abcb1a , Abcc3 , Cbr1 , Xdh Hepatomegaly Abcc3 , Nos3 hepatopulmonary syndrome Nos3 human immunodeficiency virus infectious disease Abcb1a Huntington's disease Nos3 Hyperemia Nos3 hyperglycemia Nos3 , Nqo1 hyperinsulinism Nos3 Hyperoxaluria Xdh Hyperoxia Nos3 , Nqo1 Hyperoxic Lung Injury Nqo1 , Xdh hyperprolactinemia Abcc3 hypertension Abcc1 , Nos3 , Nqo1 , Ralbp1 , Xdh Hypertension Resistant to Conventional Therapy Nos3 Hypertension, Pregnancy-Induced Nos3 Hypertriglyceridemia Nos3 hypertrophic cardiomyopathy Ndufs2 hyperuricemia Abcg2 , Xdh Hypotension Por , Xdh Hypotension, Orthostatic Abcb1a hypothyroidism Nos3 Hypoxia Nos3 impotence Nos3 Inflammation Abcb1a inflammatory bowel disease 13 Abcb1a inherited metabolic disorder Ndufs2 Insulin Resistance Nos3 interstitial nephritis Xdh intestinal perforation Nos3 Intestinal Reperfusion Injury Nos3 , Nqo1 , Xdh Intimal Hyperplasia Nos3 intracranial aneurysm Nos3 Intracranial Hemorrhages Nos3 invasive ductal carcinoma Abcb1a irritable bowel syndrome Nos3 irritant dermatitis Cbr1 ischemia Nos3 , Xdh juvenile rheumatoid arthritis Slc22a16 kidney disease Abcb1a , Abcc3 , Nqo1 kidney failure Xdh Kidney Neoplasms Abcb1a Kidney Reperfusion Injury Nos3 , Nqo1 , Xdh Kuhnt-Junius degeneration Nos3 Lead Poisoning Nqo1 learning disability Por Leber hereditary optic neuropathy Ndufs2 Left Ventricular Hypertrophy Nos3 , Nqo1 , Xdh Leigh disease Ndufs2 , Ndufs3 , Ndufs7 Leigh Syndrome Due To Mitochondrial Complex I Deficiency Ndufs3 , Ndufs7 leiomyoma Nos3 Lesch-Nyhan syndrome Xdh leukemia Akr1c3 , Nqo1 Limb Ischemia Nos3 liver benign neoplasm Nqo1 liver cirrhosis Nos3 , Nqo1 liver disease Nqo1 Liver Injury Abcg2 Liver Reperfusion Injury Nos3 , Xdh long QT syndrome Nos3 lung cancer Nqo1 lung disease Nos3 , Nqo1 Lung Injury Nqo1 Lung Neoplasms Nqo1 Lung Reperfusion Injury Nos3 , Nqo1 lymphangioleiomyomatosis Nos3 Lymphatic Metastasis Nos3 Lymphoma, Extranodal NK-T-Cell Abcb1a macular degeneration Nqo1 macular retinal edema Nos3 major depressive disorder Xdh male infertility Nos3 malignant glioma Nos3 Mammary Neoplasms, Experimental Abcb1a , Abcg2 , Xdh megakaryocytic leukemia Abcg2 membranous glomerulonephritis Nqo1 mental depression Nqo1 Mercury Poisoning Nqo1 Metabolic Syndrome Nos3 microphthalmia Ralbp1 middle cerebral artery infarction Nqo1 , Xdh migraine Nos3 mitochondrial complex I deficiency Ndufs2 , Ndufs3 , Ndufs7 mitochondrial encephalomyopathy Ndufs2 Mouth Neoplasms Cbr3 multiple myeloma Abcg2 , Nqo1 Multiple Organ Failure Xdh multiple sclerosis Ndufs2 muscular disease Xdh Musculoskeletal Abnormalities Por myelodysplastic syndrome Nqo1 myeloid leukemia Nqo1 myeloid neoplasm Akr1c3 , Nqo1 myocardial infarction Nos3 Myocardial Ischemia Nos3 , Ralbp1 Myocardial Reperfusion Injury Nos3 , Xdh Nasal Polyps Abcb1a , Nos3 Nausea Abcb1a Neoplasm Metastasis Abcb1a , Nos3 Neoplasms, Hormone-Dependent Akr1c3 nephritis Nos3 nephroblastoma Abcb1a Nephrosis, Puromycin Aminonucleoside Xdh Nerve Degeneration Xdh nervous system disease Abcb1a , Abcc2 , Abcg2 neural tube defect Por neuroblastoma Abcb1a neurodegenerative disease Nqo1 neutropenia Abcb1a non-small cell lung carcinoma Abcb1a , Abcc2 , Nqo1 nonalcoholic fatty liver disease Abcb1a , Abcc2 , Abcc3 , Nqo1 obesity Akr1c3 , Nos3 , Nqo1 , Xdh obstructive sleep apnea Abcb1a , Nos3 Occupational Diseases Nqo1 optic atrophy Ndufs3 Ovarian Neoplasms Abcb1a , Abcg2 , Nos3 Overactive Urinary Bladder Nqo1 overnutrition Nos3 Pain Abcb1a , Nos3 Pain, Postoperative Abcb1a pancreatic cancer Abcc2 , Abcc3 pancreatitis Xdh Pancreatitis, Experimental, Chronic Nqo1 papilloma Nqo1 Parkinson's disease Abcb1a , Nqo1 Parkinsonian Disorders Ndufs3 Perennial Allergic Rhinitis Nos3 perinatal necrotizing enterocolitis Abcb1a , Akr1a1 , Nos3 peripheral nervous system disease Abcb1a , Abcc1 peritonitis Xdh persistent fetal circulation syndrome Nos3 Phyllodes Tumor Nos3 placental abruption Nos3 pleomorphic xanthoastrocytoma Abcb1a , Por Pneumoperitoneum Xdh Poisoning Abcb1a , Nqo1 polycystic kidney disease Nos3 polycystic ovary syndrome Akr1c3 portal hypertension Nos3 , Xdh pre-eclampsia Akr1c3 , Nos3 precursor B lymphoblastic lymphoma/leukemia Akr1c3 precursor lymphoblastic lymphoma/leukemia Abcb1a , Abcc2 , Abcg2 , Nos3 , Nqo1 precursor T-lymphoblastic lymphoma/leukemia Abcg2 , Akr1c3 primary biliary cirrhosis Abcc2 , Abcg2 , Nos3 primary open angle glaucoma Nos3 prostate cancer Akr1c3 Prostatic Neoplasms Akr1c3 , Cbr1 , Nos3 , Nqo1 , Ralbp1 prostatitis Nqo1 protein-losing enteropathy Xdh pseudoxanthoma elasticum Abcc1 pulmonary edema Nos3 pulmonary embolism Nos3 , Xdh pulmonary emphysema Nos3 , Nqo1 pulmonary eosinophilia Nos3 pulmonary hypertension Nos3 Pulmonary Hypertension, Hypoxia-Induced Nos3 Radiation Pneumonitis Nos3 renal cell carcinoma Abcb1a , Abcg2 renal fibrosis Nqo1 , Xdh renal hypertension Nos3 Renal Ischemia Xdh renovascular hypertension Nos3 Reperfusion Injury Abcb1a , Abcg2 , Nos3 , Xdh respiratory allergy Nos3 Retina Reperfusion Injury Nos3 , Xdh retinal degeneration Nos3 retinopathy of prematurity Nos3 rheumatoid arthritis Abcb1a , Abcc2 , Abcc3 , Abcg2 Right Ventricular Hypertrophy Nos3 schizophrenia Abcc1 secondary hyperparathyroidism Abcg2 secondary Parkinson disease Abcb1a Sepsis Nos3 , Xdh sex differentiation disease Akr1c3 Shock Xdh Shock, Hemorrhagic Nos3 sickle cell anemia Nos3 small cell carcinoma Nqo1 Smith-Magenis syndrome Abcc3 Spinal Cord Compression Nos3 Spinal Cord Injuries Nos3 , Nqo1 , Xdh spinocerebellar ataxia type 17 Nqo1 status epilepticus Abcb1a , Abcc2 , Abcg2 , Nqo1 Stomach Neoplasms Akr1c3 , Nos3 Stroke Nos3 Subarachnoid Hemorrhage Nos3 , Nqo1 telangiectasis Nos3 temporal lobe epilepsy Abcb1a Testis Reperfusion Injury Nos3 , Xdh thrombocytopenia Xdh Thromboembolism Nos3 Thrombotic Microangiopathies Nos3 toxic encephalopathy Abcb1a , Abcg2 , Nqo1 transient cerebral ischemia Nos3 , Nqo1 Translocation, Genetic Abcb1a Transplant Rejection Nos3 , Xdh type 1 diabetes mellitus Nos3 type 2 diabetes mellitus Abcb1a , Abcc2 , Nos3 uremia Nos3 ureteral obstruction Nos3 , Nqo1 urinary bladder cancer Nos3 , Nqo1 , Por , Ralbp1 , Xdh Urologic Neoplasms Nqo1 vasculitis Nos3 Vaso-occlusive Crisis Nos3 Venous Thrombosis Nos3 Ventricular Dysfunction, Right Nos3 Ventricular Premature Complexes Nos3 Ventricular Tachycardia Nos3 vestibular disease Nos3 visual epilepsy Abcb1a , Abcc2 , Nqo1 Vomiting Abcb1a Vulvar Neoplasms Nos3 Warfarin Sensitivity Nqo1 Wounds, Penetrating Xdh xanthinuria Xdh Xanthinuria, Type I Xdh Xanthinuria, Type II Xdh
