ABC transporters: circadian rhythms and sexrelated differences

Abstract

ABC (ATP-binding cassette) transporter superfamily contains membrane proteins transporting substrates across the plasma membrane including drugs, xenobiotics and endogenous compounds. ABC proteins are ATP-dependent primary active transporters that pump substrates across the membranes. In addition to the expression of ABC transporters in intestinal segments, liver and kidney which are responsible for absorption, metabolism and elimination, these are also expressed in other important tissues such as brain and heart. P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP), the important members of ABC superfamily, play significant role in pharmacokinetics and detoxification of drugs and drug metabolites facilitating intestinal secretion, and excretion of drugs into the bile and urine in liver and kidney respectively. In addition to expression of ABC proteins in healthy tissues, they are also expressed in tumor cells, and cause multidrug resistance (MDR) by extruding antineoplastic drugs out of tumor cells and reducing the accumulation of drugs in tumor tissues, thus result in failure of chemotherapy. Expression of ABC transporters in healthy tissues shows circadian rhythm, and activities of these transporters increase and decrease depending on the time of day. Thus, the efficacy and toxicity of drugs transported by ABC transporters change depending on application time of drugs. Additionally, sex-related differences in ABC transporters, not only for drug metabolizing enzymes, are seen as an important factor in the variation of drug effectiveness and drug-induced response. Intra-day and gender-related changes in the functional activity of transporters are important parameters that may change the pharmacological effects and toxicity of drugs.