Chronic Alcohol Consumption Increased Bile Acid Levels in Enterohepatic Circulation and Reduced Efficacy of Irinotecan

Abstract

Aims To investigate the effect of ethanol intake on the whole enterohepatic circulation (EHC) of bile acids (BAs) and, more importantly, on pharmacokinetics of irinotecan. Methods The present study utilized a mouse model administered by gavage with 0 (control), 240 mg/100 g (30%, v/v) and 390 mg/100 g (50%, v/v) ethanol for 6 weeks, followed by BA profiles in the whole EHC (including liver, gallbladder, intestine and plasma) and colon using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Pharmacokinetic parameters of irinotecan were measured after administration of irinotecan (i.v. 5 mg/kg) on alcohol-treated mice. Results The results showed that compared with the control group, concentrations of most free-BAs, total amount of the three main forms of BAs (free-BA, taurine-BA and glycine-BA) and total BAs (TBAs) in 50% ethanol intake group were significantly increased, which are mostly attributed to the augmentation of free-BAs and taurine-BAs. Additionally, the TBAs in liver and gallbladder and the BA pool were markedly increased in the 30% ethanol intake group. Importantly, ethanol intake upregulated the expression of BA-related enzymes (Cyp7a1, Cyp27a1, Cyp8b1 and Baat) and transporters (Bsep, Mrp2, P-gp and Asbt) and downregulated the expression of transporter Ntcp and nuclear receptor Fxr in the liver and ileum, respectively. Additionally, 50% ethanol intake caused fairly distinct liver injury. Furthermore, the AUC0–24 h of irinotecan and SN38 were significantly reduced but their clearance was significantly increased in the disrupted EHC of BA by 50% ethanol intake. Conclusions The present study demonstrated that ethanol intake altered the expression of BA-related synthetases and transporters. The BA levels, especially the toxic BAs (chenodeoxycholic acid, deoxycholic acid and lithocholic acid), in the whole EHC were significantly increased by ethanol intake, which may provide a potential explanation to illuminate the pathogenesis of alcoholic liver injury. Most importantly, chronic ethanol consumption had a significant impact on the pharmacokinetics (AUC0–24 h and clearance) of irinotecan and SN38; hence colon cancer patients with chronic alcohol consumption treated with irinotecan deserve our close attention.

Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

“… 7 In rodents, ethanol consumption altered BA biosynthesis and transporters. 8 , 9 , 10 Emerging evidence has shown that BA signaling contributes to the development of AALD. For example, alcohol feeding aggravated liver inflammation and injury in mice deficient for cholesterol 7α-hydroxylase (Cyp7a1), a rate-limiting enzyme in BA synthesis.…”

Bile Acids, Gut Microbes, and the Neighborhood Food Environment—a Potential Driver of Colorectal Cancer Health Disparities

“…Consistent with this, a recent study investigating chronic ethanol consumption on enterohepatic circulation in rats observed that alcohol abuse (50%, vol/vol, ethanol) increased the abundance of total BAs in all compartments studied (colon, gallbladder, intestine, liver, and plasma). This BA pool expansion was associated with increased expression of genes that upregulate BA production, including Cyp7a1 , Cyp27a1 , Cyp8b1 , and Baat ( 71 ). Several studies have established changes in gut microbial composition in response to alcohol consumption, most notably an increase in proteobacteria and fusobacteria ( 72 ).…”

“…The metabolites of alcohol metabolism promote genetic damage and instability and induce changes to cellular pathways commonly observed in CRC. Of more recent interest is the effect of chronic alcohol consumption on the composition of circulating BAs and their concomitant associations with cancer development ( 71 ). In the ATBC study, alcohol consumption is positively associated with circulating primary and secondary BAs ( 40 ).…”

“…In a study that examined the neighborhood food environment in four states, higher SES neighborhoods had 3 times fewer places that served alcohol than lower SES neighborhoods ( 97 ). This is problematic, as one of the multiple negative impacts of alcohol consumption is that it increases expression of genes that induce bile acid production ( 71 ). Additionally, a systematic review investigating differences in accessibility to convenience foods concluded that lower-SES neighborhoods had higher access to fast food outlets and that fast foods were more heavily advertised in AA/B neighborhoods regardless of SES ( 99 ).…”

Review article: therapeutic aspects of bile acid signalling in the gut‐liver axis

“…81 Third, FXR-induced upregulation of SHP represses the expression of NTCP in hepatocytes in vitro, 82 which was confirmed in vivo using BDL rats and mice, indicating that this regulatory mechanism protects hepatocytes from BA toxicity (Figure 3). [83][84][85][86] Interestingly, a recent in vitro study suggested that endoplasmic reticulum stress may also downregulate NTCP independently from FXR, 87 which may be relevant apart from "primary" cholestatic liver diseases such as PBC, 88 since NTCP was also downregulated in mice fed with ethanol, 89 a rat model of non-alcoholic fatty liver disease (NAFLD), 90 and patients with alcohol(ALD)-and hepatitis C virus-associated cirrhosis, as compared to healthy liver tissue. 91,92 NTCP has emerged as an important therapeutic target since it was identified as an entry point for the hepatitis B (HBV) and D (HDV) virus.…”