Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The defense mechanisms responsible for protecting the body from endogenous toxins are also involved in the metabolism of drugs and are composed of phase I and phase II drug metabolizing enzymes, as well as drug transporters. Numerous drugs and chemicals have been shown to modulate the expression of the genes involved in these three drug-detoxifying processes. Induction of these genes contributes to both auto-induction of drug clearance and to drug-drug interactions in combination therapies. The orphan nuclear receptors PXR (pregnane X receptor) and CAR (Constitutive androstane receptor) are xenosensors that mediate drug-induced changes by increasing transcription of genes that are involved in drug clearance and disposition. Co-administration of drugs, one of which is a nuclear receptor agonist or antagonist, can either lead to altered clearance of the second drug and severe toxicity, or a loss of therapeutic efficacy or an imbalance in physiological substrate concentrations, providing a novel molecular mechanism for drug-drug interactions. Thus, genetic variability in these nuclear receptors will contribute to human variation in the magnitude of clinically significant drug-drug interactions. This review describes common PXR and CAR genetic variants that have been identified to date in the human population and the functional consequence of these variant alleles. In addition, alternatively spliced variants of PXR and CAR that may also contribute to individual variability as well as tissue specific expression of these receptors are also described. Identification of PXR and CAR genetic variants and alternatively spliced mRNAs may ultimately allow predictions of interindividual differences in target gene induction and drug-drug interactions.
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PMID:Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. 1610 75

A key role for nitric oxide (NO) in penile erection is well established, but the relative roles of the neuronal NO synthase (nNOS) versus endothelial forms of NOS are not clear. nNOS- and endothelial NOS-deficient mice maintain erectile function and reproductive capacity, questioning the importance of NO. Alternatively, residual NO produced by shorter transcripts in the nNOS(-/-) animals might suffice for normal physiologic function. We show that the beta splice variant of nNOS elicits normal erection despite a decrease in stimulus-response characteristics and a 5-fold increased sensitivity to the NOS inhibitor, l-NAME. Residual nNOSbeta generates only 10% of the normal NO level in vitro but produces citrulline and diaphorase staining reflecting in vivo NOS activity in pelvic ganglion nerves that is comparable to WT animals. Thus, alternatively spliced forms of nNOS are major mediators of penile erection and so may be targets for therapeutic intervention.
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PMID:Alternatively spliced neuronal nitric oxide synthase mediates penile erection. 1648 73

Porcine constitutive androstane receptor (CAR; NR1I3) was cloned and compared for homology and activity with mouse and human CAR (mCAR, hCAR). Porcine CAR (pgCAR) was 86% and 75% homologous to hCAR at the nucleotide and protein levels. Five alternatively spliced variants of pgCAR were identified, each of which generated a truncated protein product. Real-time polymerase chain reaction (PCR) analyses showed that these variants were present in pig liver cDNA samples from 4.61% to 9.20% of total pgCAR. pgCAR and hCAR responded similarly to more ligands than did hCAR and mCAR. The known hCAR agonist (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) activated pgCAR, while the murine agonist 1,4 bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) had no effect. 5beta-dihydrotestosterone was identified as a novel inverse agonist of both pgCAR and hCAR. pgCAR splice variant 2 (SV2) had a dose-dependent dominant negative effect on the activity of wild-type pgCAR in dual luciferase assays. SV2 had no effect against pgPXR (pregnane X receptor) or pgFXR (farnesoid X receptor) activity when using PXR- or FXR-specific reporters.
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PMID:Characterization of the porcine constitutive androstane receptor (CAR) and its splice variants. 1992 82