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.
N1 - Funding Information:
1This investigation was supported in part by USPHS Grants ES 09140 (to SVS), awarded by the National Institute of Environmental Health Sciences, and CA 76348 (to SVS), CA 63600 (to SA), and Cancer Center Support Grant CA 17613, awarded by the National Cancer Institute. 2To whom correspondence should be addressed. Fax: (412) 232-5753. E-mail: ssingh@mercy.pmhs.org.
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 -