Quinacrine Is Mainly Metabolized to Mono-Desethyl Quinacrine by Cyp3a4/5 and Its Brain Accumulation Is Limited by P-Glycoprotein

Huang, Yong; Okochi, Hideaki; May, Barnaby C. H.; Legname, Giuseppe; Prusiner, Stanley B.; Benet, Leslie Z.; Guglielmo, B. Joseph; Lin, Emil T.

doi:10.1124/dmd.105.008664

Cited by 47 publications

(45 citation statements)

References 23 publications

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“…First, the effects of "antiprion" compounds are clearly species/strain-dependent, in that drugs found to restrain prions in one situation may improve replicative ability in another. Based on initial reports of quinacrine's effects on mouse prion propagation in cell culture, a plethora of studies were designed to discern the mechanism of its presumed antiprion effects (19,20,(29)(30)(31)(38)(39)(40)(41)(42)(43)(44)(45), to assess its pharmacokinetics (21,36,42,46) and to derive similar compounds with improved antiprion efficacy (18,20,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). These studies continue to this day, despite multiple failed clinical studies in patients with human prion diseases (10)(11)(12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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Section: Discussionmentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…and S.B.P., unpublished data). During studies of Qa metabolism in mice, we found that Qa efflux from the brain is controlled by multidrug-resistant (MDR) proteins, members of the P-glycoprotein ATP binding cassette transporters (22). Disappointingly, MDR-deficient mice accumulate high levels of Qa in their brains but fail to show prolonged survival after prion inoculation (K.G.…”

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confidence: 99%

A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

Spilman¹,

Lessard

Sattavat³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrP Sc ) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the ␥-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this ␥-secretase inhibitor (GSI) might prevent dendritic degeneration in mice with scrapie. At 50 d postinoculation with Rocky Mountain Laboratory (RML) prions, mice were given GSI orally for 43-60 d. Because we did not expect GSI to produce a reduction of PrP Sc levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrP Sc formation in cultured cells. The combination of GSI and Qa reduced PrP Sc by Ϸ95% in the neocortex and hippocampus but only Ϸ50% in the thalamus at the site of prion inoculation. The GSI plus Qa combination prevented dendritic atrophy and loss, but GSI alone did not. Even though GSI reduced NICD levels to a greater extent than GSI plus Qa, it was unable to prevent dendritic degeneration. Whether a balance between NICD and dendrite growth-stimulating factors was achieved with GSI plus Qa but not GSI alone remains to be determined. Although the combination of GSI and Qa diminished PrP Sc in the brains of RML-infected mice, GSI toxicity prevented us from being able to assess the effect the GSI plus Qa combination on incubation times. Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined.Creutzfeldt-Jakob disease ͉ neuropathology ͉ prion disease ͉ therapy ͉ scrapie

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“…For these 73 (Table 3). [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] The mean (± S.D.) and median CYP3A5/CYP3A4 ratios of the metabolic activities in these 47 reactions were 0.69 ± 1.23 and 0.28, respectively.…”

Section: Metabolic Activity Of Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Niwa

Murayama

Yamazaki

2010

JOURNAL OF HEALTH SCIENCE

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A meta-analysis was performed on the reported literature regarding followings. First, values of the MichaelisMenten constants (K m ), maximal velocities (V max ), and intrinsic clearance (V max /K m ) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (K i ); and third, maximum inactivation rate constants (k inact ) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of K m , V max , and V max /K m values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the V max and V max /K m values for P450 3A5 were more than twice those for P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

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Quinacrine Is Mainly Metabolized to Mono-Desethyl Quinacrine by Cyp3a4/5 and Its Brain Accumulation Is Limited by P-Glycoprotein

Cited by 47 publications

References 23 publications

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

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