Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy

Li, Feng; Lu, Jie; Cheng, Jie; Wang, Laiyou; Matsubara, Tsutomu; Csanaky, Iván L.; Klaassen, Curtis D.; Gonzalez, Frank J.; Ma, Xiaochao

doi:10.1038/nm.3104

Cited by 137 publications

(128 citation statements)

References 19 publications

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“…Recently, mouse models using PXB mice and PXR-humanized mice have been proven to be powerful tools for investigating the DDIs relevant to human drug-metabolizing enzymes, such as CYP3A4 and CYP2B6 (61)(62)(63). In accordance with these studies, the inductive effect of RIF and inhibitory effect of KTC on CYP3A4 activity were observed in HepaRG cells, implying that the ex vivo studies reflect experiments using mouse models (62,64) (Table 3; see also Table S3 in the supplemental material).…”

Section: Discussionmentioning

confidence: 61%

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

Horita

Doi

2014

Antimicrob Agents Chemother

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Predicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in the in vitro screening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused by WHO group 5 drugs, thioamides, and p-aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at >0.25 M in HepaRG cells, while an inhibitory effect was observed at 1.69 M in the in vitro screening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism.

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Section: Discussionmentioning

confidence: 61%

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

Horita

Doi

2014

Antimicrob Agents Chemother

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“…These receptors are important for regulation of both ALAS1 and P450s in the liver by drugs and other chemicals. Therefore, ligands of these nuclear receptors can upregulate ALAS1 expression and increase PPIX and heme synthesis (Fraser et al, 2003;Li et al, 2013).…”

Section: Regulation Of Ppix Biosynthesis Through Alasmentioning

confidence: 99%

Protoporphyrin IX: the Good, the Bad, and the Ugly

Sachar

Anderson

2015

Journal of Pharmacology and Experimental Therapeutics

163

148

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Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

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“…Dicha combinación da lugar a una mayor actividad de transaminasas, fosfatasa alcalina, a una mayor tasa de inhibición de secreción biliar, de síntesis y excreción de ácidos biliares, bilirrubina y colesterol con la bilis; también a un aumento en el nivel de productos de peroxidación de lípidos de membrana (39) . Actualmente, se ha descubierto que el cotratamiento de R+I provoca la acumulación endógena de una hepatotoxina: la protoporfirina IX (40) .…”

Section: Discusionunclassified

Efecto hepatoprotector del Asparagus officinalis (Espárrago verde) en daño inducido por fármacos antituberculosos

Mezones¹,

Lara²,

Paredes³

et al. 2016

Rev. per. med. integr.

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RESUMENObjetivos. Evaluar el efecto hepatoprotector del extracto acuoso del Asparagus officinalis (AO) en daño inducido por fármacos antituberculosos. Materiales y métodos. Diseño experimental, se utilizó ratas Holtzman macho (n= 32) y tallos de AO. Se conformó cuatro grupos de ratas (n=8): G1: control con solución salina fisiológica (SSF) por vía oral (VO), G2, G3 y G4 con AO a dosis de 25, 50 y 100 mg/kg respectivamente; todos los grupos recibieron isoniazida (I) y rifampicina (R) a razón de 50 mg/kg durante 21 días. Se realizó punción cardiaca para evaluación seriada de enzimas hepáticas; finalmente, las ratas fueron sacrificadas para análisis histopatológico. Se evaluó la variación de peso, cambios en heces y orinas. Niveles de transaminasas (ALT y AST), bilirrubina total (BT), evaluación macroscópica de hígado y estructura hepatocelular. Se aplicó la prueba paramétrica de ANOVA y post-hoc Sheffe, y las no paramétricas de Kruskal-Wallis y Mann Whitney. El análisis se realizó con el paquete estadístico SPSS V20 y se consideró significativo un p<0,05. Resultados. El peso disminuyó 8,06% en el grupo G1. Las heces y orinas fueron de color marrón oscuro en mayor porcentaje en G1. Los niveles de ALT y AST resultaron mayores en G1 a los días 11 y 21 con respecto a G2, G3 y G4 (prueba ANOVA [p< 0,01], Scheffe (p< 0,01)). El Grupo G1 presentó severa infiltración de células inflamatorias, marcada congestión alrededor de vena centrolobulillar y severa dilatación de sinusoides a diferencia de G2, G3 y G4. Conclusiones. En condiciones experimentales el extracto acuoso del Asparagus officinalis tiene efecto hepatoprotector ante el daño inducido por fármacos antituberculosos (I + R).Palabras clave: Asparagus officinalis; Enfermedad Hepática Inducida por Drogas; Sustancias Protectoras /uso terapéutico; Antituberculosos/efectos adversos (Fuente: DeCS Bireme). HEPATOPROTECTIVE EFFECT OF Asparagus officinalis (GREEN ASPARAGUS) ON DAMAGE INDUCED BY TUBERCULOSTATIC AGENTS ABSTRACTObjectives. Evaluate the hepatoprotective effect of aqueous extract from Asparagus officinalis (AO) in damage induced by antituberculosis drugs. Material and methods. Experimental study. 32 Holtzman male rats were divided into four groups of 8; G1: control with oral administration (VO) of physiological saline solution (SSF), G2, G3 and G4 with AO at doses of 25, 50 and 100 mg/kg respectively; all groups received Isoniazid (I) and rifampin (R) at 50 mg/kg for 21 days. Cardiac puncture was performed for serial assessment of liver enzymes, finally they were sacrificed for histopathological analysis. Variations in weight, feces and urine, transaminase levels (ALT and AST), total bilirubin (BT) macroscopic evaluation of the liver and hepatocellular structure were evaluated. Parametric tests of ANOVA and post-hoc Sheffey and nonparametric Kruskal-Wallis and Mann Whitney were applied, considering p <0.05 as significant, with SPSS v20. Results. The weight decreased 8.06% in group G1. Feces and urine were dark brown in higher percentage in G1. ALT and AST levels...

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Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy

Cited by 137 publications

References 19 publications

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

Protoporphyrin IX: the Good, the Bad, and the Ugly

Efecto hepatoprotector del Asparagus officinalis (Espárrago verde) en daño inducido por fármacos antituberculosos

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