Search

The literature provides compelling evidence pointing to tight metabolic interactions between retinoids and xenobiotics. These are extensive and important for understanding xenobiotic actions in the body. Within the body, retinoids affect xenobiotic metabolism and actions and conversely, xenobiotics affect retinoid metabolism and actions. This article summarizes data that establish the importance of retinoid-dependent metabolic pathways for sustaining the body's responses to xenobiotic exposure, including the roles of all-trans- and 9-cis-retinoic acid for protecting mammals from harmful xenobiotic effects and for ensuring xenobiotic elimination from the body. This review will also consider molecular mechanisms underlying xenobiotic toxicity focusing on how this may contribute to retinoid deficiency and disruption of normal retinoid homeostasis. Special attention is paid to xenobiotic molecular targets (nuclear receptors, regulatory proteins, enzymes, and transporters) which affect retinoid metabolism and signaling.

Hepatocellular carcinoma (HCC) is a major health issue in many countries. The prognosis of HCC is still poor due to its high recurrence rate and its resistance to chemotherapy. Retinoids have long been known to have a connection with liver diseases, including HCC. Many experimental and clinical investigations have demonstrated associations between retinoids and hepatic disease, including the loss of retinoid activity in HCC cell lines and decreased hepatic retinoid stores and altered retinoid signaling in patients with cirrhosis and HCC. Based on these findings, preclinical and clinical investigations of retinoid effects on HCC have been undertaken. Recently, clinical trial results for the use of a synthetic retinoid, acyclic retinoid (ACR), to prevent HCC recurrence were published. In addition, extensive experimental studies on the action of retinoids in liver disease, including chronic viral hepatitis and non-alcoholic fatty liver disease (NAFLD), which lead to HCC have been performed. In the first section of this review, we will summarize the effectiveness and roles of retinoid for treating liver disease and blocking HCC. Subsequently, we will focus on ACR actions in blocking HCC.

Distribution of vitamin A throughout the body is important to maintain retinoid function in peripheral tissues and to ensure optimal vision. A critical step of this process is the transport of vitamin A across cell membranes. Increasing evidence indicates that this process is mediated by a multidomian membrane protein that is encoded by the stimulated by retinoic acid 6 (STRA6) gene. Biochemical studies revealed that STRA6 is a transmembrane pore which transports vitamin A bidirectionally between extra- and intracellular retinoid binding proteins. Vitamin A accumulation in cells is driven by coupling of transport with vitamin A esterification. Loss-of-function studies in zebrafish and mouse models have unraveled the critical importance of STRA6 for vitamin A homeostasis of peripheral tissues. Impairment in vitamin A transport and uptake homeostasis are associated with diseases including type 2 diabetes and a microphthalmic syndrome known as Matthew Wood Syndrome. This review will discuss the advanced state of knowledge about STRA6's biochemistry, biology and association with disease.