TY - JOUR
T1 - Metabolomics approach discriminates toxicity index of pyrazinamide and its metabolic products, pyrazinoic acid and 5-hydroxy pyrazinoic acid
AU - Rawat, A.
AU - Chaturvedi, S.
AU - Singh, A. K.
AU - Guleria, A.
AU - Dubey, D.
AU - Keshari, A. K.
AU - Raj, V.
AU - Rai, A.
AU - Prakash, A.
AU - Kumar, U.
AU - Kumar, D.
AU - Saha, S.
N1 - Publisher Copyright:
© 2017, © The Author(s) 2017.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Pyrazinamide (PYZ)—an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis—is 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.
AB - Pyrazinamide (PYZ)—an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis—is 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.
KW - 5-hydroxy pyrazinoic acid
KW - hepatotoxicity
KW - metabolomics
KW - NMR
KW - Pyrazinamide
UR - https://www.scopus.com/pages/publications/85035042315
U2 - 10.1177/0960327117705426
DO - 10.1177/0960327117705426
M3 - Article
C2 - 28425350
AN - SCOPUS:85035042315
SN - 0960-3271
VL - 37
SP - 373
EP - 389
JO - Human and Experimental Toxicology
JF - Human and Experimental Toxicology
IS - 4
ER -
