Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors

Pellinen, Pertti; Honkakoski, Paavo; Stenbäck, Frej; Niemitz, Matthias; Alhava, Esko; Pelkonen, Olavi; Lang, Matti A.; Pasanen, Markku

doi:10.1016/0926-6917(94)90078-7

Cited by 63 publications

(58 citation statements)

References 26 publications

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“…Therefore, only weak activation by pure NR ligands of Cyp2b10 gene might be expected in vivo. Indeed, hepatocytes transfected with a PBREM construct showed only 2-fold activation after PCN treatment (Xie et al, 2000b;Smirlis et al, 2001); hepatic CYP2B10 was induced 37-fold by PB but only 7-fold by PCN (Pellinen et al, 1994); CYP2B10 mRNA induction was not affected either by thyroid hormone or by retinoic acid in mouse hepatocytes ); T3 does not seem to affect PBREM or its associated factors in rats (Ganem et al, 1999). The identity of 5Ј-flanking nucleotides in DR4 motifs is important for TR-mediated activation (Harbers et al, 1996;Zhang and Lazar, 2000) and this property may explain the discrepancy between the strong binding and inefficient function by TR␣ on PBREM.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Mouse and Human Phenobarbital-Responsive Enhancer Module by Nuclear Receptors

et al. 2002

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The constitutive androstane receptor (CAR) regulates mouse and human CYP2B genes through binding to the direct repeat-4 (DR4) motifs present in the phenobarbital-responsive enhancer module (PBREM). The preference of PBREM elements for nuclear receptors and the extent of cross-talk between CAR and other nuclear receptors are currently unknown. Our transient transfection and DNA binding experiments indicate that binding to DR4 motifs does not correlate with the activation response and that mouse and human PBREM are efficiently 'insulated' from the effects of other nuclear receptors despite their substantial affinity for DR4 motifs. Certain nuclear receptors that do not bind to DR4 motifs, such as peroxisome proliferator-activated receptor-␣ and farnesoid X receptor, can suppress PBREM function via a coactivator-dependent process that may have relevance in vivo. In competition experiments, mouse PBREM is clearly more selective for CAR than human PBREM. Pregnane X, vitamin D, and thyroid hormone receptors can potentially compete with human CAR on human PBREM. In contrast to the selective nature of PBREM, CYP3A enhancers are highly and comparably responsive to CAR, pregnane X receptor, and vitamin D receptor. In addition, the ligand specificities of human and mouse CAR were defined by mammalian cotransfection and yeast two-hybrid techniques. Our results provide new mechanistic explanations to several previously unresolved aspects of CYP2B and CYP3A gene regulation.

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Section: Discussionmentioning

confidence: 99%

Modulation of Mouse and Human Phenobarbital-Responsive Enhancer Module by Nuclear Receptors

et al. 2002

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“…Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010). (Pellinen et al, 1993) Chloroform Anesthetic/Teflon (Camus et al, 1996) Cocaine Topical anesthetic (Pellinen et al, 1994a(Pellinen et al, , 1994b) Ethanol Fuel, beverage, and antiseptic (Lu et al, 2010) Phenobarbital Barbiturate and anticonvulsant (Hahnemann et al, 1992;Salonpää et al, 1994) Pyrazole Precursor for various medicines (Juvonen et al, 1985;Nichols and Kirby, 2008 (Cai et al, 2002) Buthionine sulfoximine Drug used in chemotherapy to reduce levels of glutathione (Gilmore et al, 2003) pregnenolone 16a-carbonitrile (PCN) Pregnane X receptor (PXR) agonist or antiglucocorticoid (Cai et al, 2002) Rifampicin Bactericidal antibiotics (Donato et al, 2000) Trans-4,5-dihydroxy-1,2-dithiane (DTTox) Intramolecular disulfide form of dithiothreitol; reducing agent (Gilmore and Kirby, 2004) (Montero et al, 1999) Bilirubin Bilirubin (BR) is the end product of heme catabolism, and heme is found in hemoglobin or other hemoproteins such as cytochromes, catalase, and a small pool of unbound free heme (Roy-Chowdhury et al, 2007). BR consists of a tetrapyrrole ( Figure D1).…”

Section: Pathophysiological States Associated With Cyp2a5mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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“…Cocaine is metabolized by several enzymatic pathways and also by non-enzymatic hydrolysis. Minor pathways include metabolism by the CYP-3A to norcocaine [43]. This metabolite may be responsible for the hepatotoxicity of cocaine [44], but the low levels formed are unlikely to contribute to systemic effects.…”

Section: Cocaine-protein Bindingmentioning

confidence: 99%

Mechanisms of Acute Cocaine Toxicity

Heard¹,

Palmer²,

Zahniser³

2008

TOPHARMJ

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Abstract:Patients with acute cocaine poisoning present with life-threatening symptoms involving several organ systems. While the effects of cocaine are myriad, they are the result of a limited number of cocaine-protein interactions, including monoamine transporter, neurotransmitter receptor and voltage-gated ion channels. These primary interactions trigger a cascade of events that ultimately produce the clinical effects. The purpose of this article is to review the primary interactions of cocaine and the effects that these interactions trigger. We also describe the progression of symptoms observed in cocaine poisoning as they relate to serum cocaine concentrations.

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Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors

Cited by 63 publications

References 26 publications

Modulation of Mouse and Human Phenobarbital-Responsive Enhancer Module by Nuclear Receptors

Modulation of Mouse and Human Phenobarbital-Responsive Enhancer Module by Nuclear Receptors

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Mechanisms of Acute Cocaine Toxicity

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