Glutathione conjugation and DNA-binding of (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in isolated rat hepatocytes

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Abstract
Isolated rat liver hepatocytes, previously depleted of glutathione (GSH) by treatment with diethylmaleate, were allowed to incorporate [3H]glycine into their GSH. Incubation of 3H-labelled cells with 14C-labelled (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene ((±)-BP-7,8-dihydrodiol) or (±)7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene ((α)-BPDE) revealed the formation of double labelled products. This together with evidence from amino acid analysis indicates formation of GSH-conjugates of the highly carcinogenic BP-derivatives. Incubation of hepatocytes isolated from 3-methylcholanthrene (MC) treated rats with 3H-labelled (±)-BP-7,8-dihydrodiol or (±)-BPDE resulted in binding of radioactivity to DNA. Reduction of the intracellular level of GSH to ∼40% of the normal level resulted in an approximate 2-fold increase in the DNA-binding of either substrate. In addition there was a concurrent decrease in the amount of GSH-conjugates formed. These data clearly demonstrate that GSH participates in conjugation reactions with carcinogenic (±)-BP-7,8-dihydrodiol and (±)-BPDE and that the intracelluilar level of GSH is important in preventing reactive intermediates from reacting with the DNA in intact cells.

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