Regulation of multidrug resistant gene expression in rodents

• Main Author: Russell, Alison L.
• Published: University of Edinburgh 1992
• Subjects: 572.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661478

P-glycoprotein (P-gp) is a member of a family of energy-dependenttransport proteins. The expression of P-gp isoforms in different tissues has been previously examined, but the physiological functions of the genes have not yet been established. Three gene isoforms have been found in rodents. These appear to be functionally distinct and only two of them are related to the multidrug resistance (mdr) phenotype displayed by tumour cells refactory to chemotherapy. Gene specific probes for each mouse isoform have allowed an analysis of mdr gene expression in normal mouse tissues. The major mdr mRNA species expressed in mouse liver is a 4.5 kb transcript encoding mdr 2. The function and factors regulating expression of this gene are unknown. Mdr 1 and mdr 3 are also expressed in mouse liver, but at lower levels. The exogenous and endogenous factors controlling the expression of mdr 1, 2 and 3 mRNA in mouse liver were examined. The regulation of mdr genes in rat liver by xenobiotics, including cytochrome P450 and glutathione S-transferase (GST) inducers, was also studied. The hepatotoxins 2-acetylaminofluorene, aflatoxin B<SUB>1</SUB> and diethylnitrosamine induced rat hepatic mdr gene expression. Diethylnitrosamine also induced hepatic and renal mdr 1 expression in the mouse. The compound, 1,4-bis[2-(3-dichlorpyridyloxy)] benzene (TCPOBOP) caused a suppression of hepatic mdr 2 and mdr 3 levels in mouse whilst inducing cytochrome P450 levels to a high extent. Long-term suppression of mdr 2 levels was also demonstrated. The anti-cancer drugs vincristine and etoposide, as well as the phenolic antioxidant butylated hydroxyanisole, known to elevate GST levels, induced mdr 2 gene expression in the mouse. Using hypophysectomised animals, it was shown that the pituitary regulates the expression of both mdr 2 and mdr 3 in mouse liver. Animal models, in which specific pituitary hormones were ablated, demonstrated that neither growth hormone nor thyroid hormone depletion reduces the expression of mdr 2. Elevation or depletion of hormones produced by the adrenal gland, using chemical treatment, also did not affect mdr 2 gene expression. The regulation of mdr 2 and 3 gene expression by the pituitary appears to be complex and may involve more than one hormone. Using a cell culture model, it was demonstrated that non-metabolisedcarcinogens do not compete with known substrates for transport across the plasma membrane. All these findings are important in elucidating the normal function and regulation of mdr genes in rodents.