Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver

Sanjay K. Srivastava, Xun Hu, Hong Xia, Sanjay Awasthi, Shantu Amin, Shivendra V. Singh

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)340-344
Number of pages5
JournalArchives of Biochemistry and Biophysics
Volume371
Issue number2
DOIs
StatePublished - Nov 15 1999

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver'. Together they form a unique fingerprint.

Cite this