Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues

Abstract

Numerous members of the cytochrome P450 (CYP) superfamily are induced after exposure to a variety of xenobiotics in human liver. We have gained considerable mechanistic insights into these processes in hepatocytes and multiple ligand-activated transcription factors have been identified over the past two decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic metabolism are also expressed in a range of extrahepatic tissues (e.g. intestine, brain, kidney, placenta, lung, adrenal gland, pancreas, skin, mammary gland, uterus, ovary, testes and prostate). Since the expression of the majority of the isoforms appears to be very low in the extrahepatic tissues in comparison with predominant expression in adult liver, the role of the enzymes in overall biotransformation and total body clearance is minor. However, basal expression and up-regulation of extrahepatic CYP enzymes can significantly affect local disposition of xenobiotics or endogenous compounds in peripheral tissues and thus modify their pharmacological/toxicological effects or affect absorption of xenobiotics into systemic circulation. The goal of this review is to critically examine our current understanding of molecular mechanisms involved in induction of xenobiotic metabolizing CYP genes of human families CYP1, CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues. We concentrate on organs such as the intestine, kidney, lung, placenta and skin, which are involved in drug distribution and clearance or are in direct contact with environmental xenobiotics. We also discuss single nucleotide polymorphisms (SNPs) of key CYPs, which at the level of transcription affect expression of the genes in the extrahepatic tissues or are associated with some pathophysiological stages or disorders in the organs.

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