Nav: Home

Xeno/endobiotic metabolism potencies vary between strains and sex in rats

February 20, 2019

In pharmaceutical companies, rats are used commonly in nonclinical studies to investigate the safety, efficacy, and pharmacokinetic profiles of drug candidates before they are entered into clinical studies. Most compounds administered via the oral route are metabolized in the liver and intestine, so the metabolism is a key determinant of pharmacokinetics.

The uridine 5'-diphospho-glucuronosyltransferase (Ugt) superfamily is one of the major groups of drug-metabolizing enzymes. They catalyze the glucuronidation of compounds to increase their water solubility and enhance their excretion through bile and urine. Ugt isoforms, categorized into Ugt1 or Ugt2 families, show different (but sometimes overlapping) substrate specificity. To understand or predict the potential for glucuronidation, information about the abundance and metabolic potencies of each Ugt isoform is required. Most importantly, quantitative evaluation of Ugts in rats has not been carried out.

To address the issue, Miki Nakajima and colleagues at Kanazawa University (Kanazawa, Japan) measured the absolute mRNA expression of Ugts in the liver and small intestine of male and female Sprague-Dawley (SD), Fischer 344 (F344), and Wistar rats by quantitative reverse transcription-polymerase chain reaction. In rats, there are eight Ugt1a isoforms (Ugt1a1, 2, 3, 5, 6, 7, 8, and 10) and seven Ugt2b isoforms (Ugt2b1, 2, 3, 6, 8, 12, and 34). The sum of mRNA expression of Ugts expressed in the liver was 2-6-fold higher than that in the small intestine regardless of the strain or sex of rats. In the liver, expression of Ugt2b mRNA represented ~80% of total expression of Ugt mRNA whereas, in the small intestine, expression of Ugt1a mRNA accounted for ~90%.

Particularly interesting data were obtained for expression of Ugts in different rat strains. Ugt2b2 was expressed specifically in the livers of Wistar rats, and resulted in twofold higher expression of total hepatic Ugt mRNA in Wistar rats than that in the other strains tested. This difference in expression between rat strains would result in differences in the glucuronidation of androsterone, lithocholic acid, and triiodothyronine, and substrates of Ugt2b2 between rat strains. Differences between strains were also observed in intestinal Ugts. Ugt2b3 expression was prominently higher in the small intestine of Wistar rats than that in the other strains tested. Ugt2b3 catalyzes the glucuronidation of aromatic primary amines. Therefore, differences in rat strains with regard to intestinal expression of Ugt2b3 could contribute to differences in rat strains in terms of drug pharmacokinetics. Therefore, Nakajima et al. provided a helpful clue for the selection of rat strains, showing that Ugt expression in Wistar rats was different from that in the other strains tested.

Hepatic expression of Ugt1a10 was significantly higher in females than in males in all strains (though the copy number was much lower than that for other isoforms) evaluated. In Wistar rats, the sum of hepatic expression of the Ugt2b isoform was higher in males than in females. In F344 rats, the sum of intestinal expression of the Ugt1a isoform was higher in males in females. Sex hormones are known to regulate expression of some Ugts, which might explain the differences in Ugt expression between sexes.

This was the first study to comprehensively quantify hepatic and intestinal mRNA expression of Ugt isoforms in SD, F344, and Wistar rats, which are used commonly for nonclinical studies. These results would be helpful for pharmaceutical scientists in choosing the strain and sex of rats for future studies.
-end-


Kanazawa University

Related Liver Articles:

The liver increases by half during the day
In mammals, the liver reaches its maximum efficiency when they are active and feed.
The IT-LIVER European consortium unveils new TGF-beta functions in liver cancer
Recent research results from the European consortium IT-Liver provide a better understanding of the role of the TGF-beta cytokine in liver cancer.
New approach to liver transplantation: Using a damaged liver to replace a dying liver
There's new hope for patients with liver disease who are waiting for a donor liver to become available for transplantation.
Unlocking a liver receptor puzzle
The nuclear receptor LRH-1 acts in the liver to regulate metabolism of fat and sugar and is a target for potential diabetes drugs.
Serious liver-related condition on the rise in the US
A new analysis reveals that cirrhosis and acute on chronic liver failure (ACLF, a deterioration of liver function in patients with cirrhosis that results in the failure of one or more organs) represent a substantial and increasing health and economic burden in the United States.
Damage to tiny liver protein function leads to heart disease, fatty liver
A UCF College of Medicine researcher has identified for the first time a tiny liver protein that when disrupted can lead to the nation's top killer -- cardiovascular disease -- as well as fatty liver disease, a precursor to cancer.
Targeted treatment for liver cancer under way
Researchers at the University of Eastern Finland and Eberhard Karls Universität Tübingen have discovered a new molecular mechanism that can be used to inhibit the growth of hepatocellular carcinoma, which is the most common liver cancer.
Transplanted liver cells protect against liver failure after massive hepatectomy surgery
Because liver failure often occurs after an extensive hepatectomy, researchers using animal models investigated safer ways to transplant liver cells post-extensive hepatectomy found that rather than transplanting cells into the liver portal vein, transplantation into an extra-hepatic site, such as the intra-mesentery, a fold of membranous tissue on the posterior wall of the abdominal cavity attached to the intestinal tract, can help protect against post-operative liver failure and aid in survival of the remaining liver.
Fatty liver disease is common
Researchers have characterized the prevalence and risk factors of fatty liver disease in patients who undergo liver transplantation.
Many diabetics don't know they have serious liver disease
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world.

Related Liver Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Setbacks
Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".