Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

Abstract

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver.

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

“…Compared with ND mice, the hepatic transcriptome of 3,5-T 2 -treated HFD mice demonstrated a specific and broad expression pattern of DME genes, but fewer differentially expressed genes. Recent studies have revealed different hepatic expression profiles of genes involved in xenobiotic processing in animal models on HFD or caloric restriction (Ghose et al 2011, Fu & Klaassen 2014. Such differences might be explained by an already modified expression of genes encoding nuclear receptors and DME in fatty liver due to pronounced oxidative stress and/or hepatic inflammation and crosstalk between proinflammatory factors and biotransformation enzymes (Pascussi et al 2003, Ghose et al 2011, which might also affect the elimination of exogenously added 3,5-T 2 .…”

“…MRP3 is responsible for the basolateral export of bile acids, xenobiotics, and glucuronide metabolites into sinusoidal blood, while OAT2 is involved in the transport of organic anions (Maher et al 2005, Zamek-Gliszczynski et al 2006, Burckhardt 2012. Hepatic expression of Abcc3 and Slc22a7 is altered by age, sex, and diet composition (Cheng et al 2008, Ghose et al 2011, Fu et al 2012, Fu & Klaassen 2014. Beside this, Dong et al (2007) demonstrated in liver of hypothyroid animals a reversed expression pattern of Slc22a7 and Abcc3, where Slc22a7 transcript levels were significantly decreased, while Abcc3 expression was increased.…”

RNA Sequencing Quantification of Xenobiotic-Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice

“…Tissues were harvested from mice between 9 a.m. and noon to minimize the diurnal variations in XPG expression (Zhang et al, 2009). Animals were not fasted before tissue collection because food restriction is known to alter XPG expression in the liver (Fu and Klaassen, 2014). Livers were collected after removing the gallbladder.…”

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

“…25 The expression and activity of many enzymes, including DMEs, usually decrease with aging. 26,27 Such reduced levels of DMEs can lead to reduced levels of drug clearance, causing enhanced drug toxicity in the elderly. 28,29 Aminopyrine N-demethylase activity was previously shown to be increased by 130% with increased age.…”