TY - JOUR
T1 - Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver
AU - Srivastava, Sanjay K.
AU - Hu, Xun
AU - Xia, Hong
AU - Awasthi, Sanjay
AU - Amin, Shantu
AU - Singh, Shivendra V.
PY - 1999/11/15
Y1 - 1999/11/15
N2 - Benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide [(+)-anti-BPDE] is believed to be the activated form of the widely spread environmental pollutant benzo[α]pyrene. Glutathione (GSH) S-transferase (GST)-catalyzed conjugation of (+)-anti-BPDE with GSH is an important mechanism in its cellular detoxification. Here, we report that the GSH conjugate of (+)-anti-BPDE [(-)- anti-BPD-SG] is a potent inhibitor (K(i) 15 μM) of class Mu human GST isoenzyme, which, among human liver GSTs, is a highly efficient detoxifier of (+)-anti-BPDE. Thus, the inhibition of GST activity by (-)-anti-BPD-SG may hinder GSH conjugation of (+)-anti-BPDE, unless the conjugate is metabolized and/or eliminated. The results of the present study show that γ- glutamyltranspeptidase (γ-GT) can metabolize (-)-anti-BPD-SG at a rate of about 0.29 nmol/min/mg protein. Our studies also show that (-)-anti-BPD-SG is transported across the human canalicular liver plasma membrane (cLPM) in an ATP-dependent manner at a rate of about 0.33 nmol/min/mg protein. The ATP- dependent transport of (-)-anti-[3H]BPD-SG across human cLPM follows Michaelis-Menten kinetics (K(m) 84 μM; V(max) 0.33 nmol/min/mg). In conclusion, the results of the present study suggest that both γ-GT-mediated metabolism and ATP-dependent canalicular transport may be important steps in overall detoxification of (+)-anti-BPDE in the human liver.
AB - Benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide [(+)-anti-BPDE] is believed to be the activated form of the widely spread environmental pollutant benzo[α]pyrene. Glutathione (GSH) S-transferase (GST)-catalyzed conjugation of (+)-anti-BPDE with GSH is an important mechanism in its cellular detoxification. Here, we report that the GSH conjugate of (+)-anti-BPDE [(-)- anti-BPD-SG] is a potent inhibitor (K(i) 15 μM) of class Mu human GST isoenzyme, which, among human liver GSTs, is a highly efficient detoxifier of (+)-anti-BPDE. Thus, the inhibition of GST activity by (-)-anti-BPD-SG may hinder GSH conjugation of (+)-anti-BPDE, unless the conjugate is metabolized and/or eliminated. The results of the present study show that γ- glutamyltranspeptidase (γ-GT) can metabolize (-)-anti-BPD-SG at a rate of about 0.29 nmol/min/mg protein. Our studies also show that (-)-anti-BPD-SG is transported across the human canalicular liver plasma membrane (cLPM) in an ATP-dependent manner at a rate of about 0.33 nmol/min/mg protein. The ATP- dependent transport of (-)-anti-[3H]BPD-SG across human cLPM follows Michaelis-Menten kinetics (K(m) 84 μM; V(max) 0.33 nmol/min/mg). In conclusion, the results of the present study suggest that both γ-GT-mediated metabolism and ATP-dependent canalicular transport may be important steps in overall detoxification of (+)-anti-BPDE in the human liver.
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U2 - 10.1006/abbi.1999.1475
DO - 10.1006/abbi.1999.1475
M3 - Article
C2 - 10545223
AN - SCOPUS:0033571711
VL - 371
SP - 340
EP - 344
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
SN - 0003-9861
IS - 2
ER -