Prevention of benzene-induced genotoxicity in bone marrow and lung cells: superiority of polyphenolic acetates to polyphenols.
Arch Toxicol. 2011 Jan 26. Epub 2011 Jan 26. PMID: 21267547
Department of Biochemistry, V. P. Chest Institute, University of Delhi, Delhi, 110007, India, firstname.lastname@example.org.
Previous investigations carried out in our laboratory have highlighted that 7,8-diacetoxy-4-methylcoumarin demonstrates a mechanism-based inhibition of cytochrome P450 (Cyt-P450) activities such as microsome-mediated aflatoxin B(1) (AFB(1)) epoxidation, dealkylation of alkylated resorufin, and toxicokinetics of benzene. 7,8-Diacetoxy-4-methylcoumarin, quercetin pentaacetate, and ellagic acid peracetate were also found to be effective in giving the protection of AFB(1)-induced genotoxicity in rat's bone marrow and lung cells possibly due to acetylation of Cyt-P450 apoprotein mediated by acetoxy drug: protein transacetylase. Later, this transacetylase was identified as calreticulin, and the acetyltransferase function of calreticulin was appropriately termed calreticulin transacetylase. In this communication, we have focused on the superiority of several classes of polyphenolic acetates to polyphenols in the modification of Cyt-P450-linked mixed function oxidases (MFOs) such as 7-ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD). Special attention has also been focused on benzene-induced genotoxicity in bone marrow and lung cells. Results clearly indicated that polyphenolic acetates demonstrated time-dependent inhibition of Cyt-P450-linked MFOs, while parent polyphenols failed to demonstrate the same. Polyphenolic acetates were found to be more superior to polyphenols in preventing benzene-induced micronuclei formation. The pattern of inhibition of Cyt-P450-dependent MFOs and benzene-induced micronuclei formation by polyphenolic acetates was found in tune with their specificities to calreticulin transacetylase. These results further substantiated that inhibition of Cyt-P450-linked MFOs and benzene-induced genotoxicity in bone marrow and lung cells by polyphenolic acetates are mediated by the action of calreticulin transacetylase that catalyzes the acetylation of concerned proteins.