Control of xeno/endobiotics-metabolizing cytochrome P450s by microRNAs

Abstract

Human cytochrome P450s (P450s, CYPs) catalyze the metabolism of xenobiotics such as drugs, environmental chemicals, and pro-carcinogens as well as endobiotics such as steroids and bile acids. To understand the reasons for inter- and intraindividual variability of drug response and adverse reaction as well as xenobiotics-related toxicity, the mechanisms of transcriptional regulation and the genetic polymorphisms of P450s have been well studied. Recently, it was discerned that microRNAs (miRNAs), endogenous short noncoding RNAs 18–24 nucleotides in length, are involved in the posttranscriptional regulation of P450s through translational repression or mRNA degradation. It became clear that miRNAs regulate P450s expression not only by a direct mechanism but also by indirect mechanisms through the regulation of transcriptional factors or modulators of enzyme activities. The miRNA-dependent regulation of P450s confers variability in detoxification of drugs and metabolic activation of environmental chemicals. In addition, it plays roles in the homeostasis of endobiotics and cancer development or progression. Polymorphisms are present not only in the mRNA but also in miRNA sequences. The miRNA-related polymorphisms may cause gain- or loss of function, resulting in change of targets of mRNA expression. The miRNA-related polymorphisms join the pharmacogenetics. Further elucidation of the role of miRNAs in drug metabolism and pharmacokinetics and drug toxicology may offer new clues for pharmacotherapy.