Abstract

The II phase metabolism, it is a set of metabolism and excretion pathways of endogenous as well as exogenous compounds including xenobiotics. UDP-glucuronyltransferases (UGTs; EC 2.4.1.17) are the most crucial representatives of II phase enzymes, which are responsible for the transformation of bilirubine and bile acids, steroids and thyroid hormones and lipids. Exogenous compounds, including drugs, carcinogens, environmental pollutants and nutrient components are also the substrates of UGTs. Deactivation of xenobiotics and the following excretion of hydrophilic conjugates is the main task of glucuronidation [1]. However, one can found glucuronides of comparable or even higher reactivity than that of the native compound. For example, morphine 6-O-glucuronide, and glucuronides of retinoids and nonsteroid anti-inflammatory drugs represent the group of active glucuronides [2]. Nearly 35% of all drugs are metabolized by UGTs. Major sites of these reaction include the liver, intestine and kidney. There were found 22 functional UGT isoforms that belong to 5 subfamilies (UGT1A, 2A, 2B, 3A and 8A). Among variety of drugs conjugated by UGTs, anticancer agents are of special interest, because of the reported differences in UGT expression in normal and tumour tissues. On the other hand, glucuronidation may also represent a mechanism of intrinsic drug resistance, as it was observed for irinotecan and methotrexate glucuronides in colon and breast cancer, respectively [3]. It has also been shown that new types of glucuronides would play a role of prodrugs, that are hydroxylyzed selectively in tumour cells [4]. Studies of our group indicated that triazolo- and imidazoacridinone antitumor agents, C-1305 and C- 1311 were glucuronidated with human liver and intestine microsomes and selectively with UGT1A10 isoform in vitro [5]. Furthermore, C-1305 glucuronide gave higher cytotoxicity than the parent drug [6]. We also demonstrated that another acridine antitumor agent, C-1748, was transformed to specific glucuronide on aliphatic hydroxyl group. Furthermore, our current results indicate that the studied antitumour acridines are able to modulate enzymatic activity of UGT. In conclusion, we demonstrated that not only drug metabolism but also drug-drug interactions should be considered in the design of acridine mediated antitumor therapy in combination with other chemotherapeutics.

Authors (6)