Metabolomics approach discriminates toxicity index of pyrazinamide and its metabolic products, pyrazinoic acid and 5-hydroxy pyrazinoic acid

被引：33

作者：

Rawat, A. ^{[1
,2
]}

Chaturvedi, S. ^{[3
,4
]}

Singh, A. K. ^{[3
]}

Guleria, A. ^{[2
]}

Dubey, D. ^{[1
,2
]}

Keshari, A. K. ^{[3
]}

Raj, V. ^{[3
]}

Rai, A. ^{[3
]}

Prakash, A. ^{[1
]}

Kumar, U. ^{[2
]}

Kumar, D. ^{[2
]}

Saha, S. ^{[3
]}

机构：

[1] Babasaheb Bhimrao Ambedkar Univ, Dept Biotechnol, Lucknow, Uttar Pradesh, India

[2] Sanjay Gandhi Post Grad Inst Med Sci Campus, Ctr Biomed Res CBMR, Raebareli Rd, Lucknow 226014, Uttar Pradesh, India

[3] Babasaheb Bhimrao Ambedkar Univ, Dept Pharmaceut Sci, Raebareli Rd, Lucknow 226025, Uttar Pradesh, India

[4] Cent Drug Res Inst, Div Pharmacokinet & Metab PKMD, CSIR, Lucknow, Uttar Pradesh, India

来源：

HUMAN & EXPERIMENTAL TOXICOLOGY | 2018年 / 37卷 / 04期

关键词：

Pyrazinamide; 5-hydroxy pyrazinoic acid; hepatotoxicity; NMR; metabolomics; NMR-BASED METABOLOMICS; IN-VITRO; HEPATOCELLULAR-CARCINOMA; INDUCED HEPATOTOXICITY; OXIDATIVE STRESS; LIVER; BLOOD; PLASMA; PHARMACOKINETICS; H-1;

D O I：

10.1177/0960327117705426

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 [卫生毒理学];

摘要：

Pyrazinamide (PYZ)an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosisis well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg(-1) for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.

引用

页码：373 / 389

页数：17

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