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Review
. 2022 Oct 17:13:1030173.
doi: 10.3389/fphar.2022.1030173. eCollection 2022.

Caffeine in liver diseases: Pharmacology and toxicology

Liang Shan  1   2   3   4 , Fengling Wang  1 , Dandan Zhai  1 , Xiangyun Meng  1 , Jianjun Liu  1 , Xiongwen Lv  2   3   4
Affiliations
Review

Caffeine in liver diseases: Pharmacology and toxicology

Liang Shan et al. Front Pharmacol. .

Abstract

We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using "caffeine" and "liver disease" as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.

Keywords: adenosine; adenosine receptor; caffeine; liver diseases; pharmacology; toxicology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Absorption, distribution, metabolism, and excretion of caffeine in the human body. Caffeine has a similar chemical structure to adenosine, and the mother nucleus of both is purine. Therefore, caffeine is a natural non-selective antagonist of adenosine, which can competitively inhibit the binding of adenosine and ARs in vivo and play different physiological functions. Caffeine is completely absorbed by the stomach and small intestine within 45 min of oral administration, following which it is distributed in all organs of the body and enters the central nervous system through the blood within 1 h. In the central nervous system, caffeine can combine with ARs and cause central nervous system excitement. Caffeine is catalyzed by CYP1A2 in the liver to produce three primary metabolites: parxanthine (82%), theobromine (11%), and theophylline (5%). The conversion process is a first-order chemical kinetic reaction, and these compounds are further metabolized and eventually excreted in the urine.
FIGURE 2
FIGURE 2
Effects and possible mechanisms of caffeine on reducing ALD, liver fibrosis, and NAFLD. The mechanism by which caffeine attenuates ALD may be related to its inhibition of the cAMP/PKA/CREB and cAMP/PKA/SRC/ERK1/2/P38 MAPK signaling pathways. The mechanism by which caffeine attenuates liver fibrosis may be related to its competitive inhibition of adenosine and AR binding (mainly A1AR, A2aAR, and A2bAR) in HSCs, which serves to reduce the levels of the extracellular fibrotic cytokines α-SMA, TGF-β, MMPs, and PDGF. Caffeine has been shown to reduce chemical toxicant-induced liver fibrosis in three animal models of liver fibrosis (DMN, CCl4, and TAA), and its effect on liver fibrosis has been further confirmed by multiple clinical trials. Caffeine attenuates HFD-induced NAFLD in mice, which has also been confirmed in several clinical trials; its mechanism may be related to the reduction of liver damage caused by the second strike and/or multiple strike.
FIGURE 3
FIGURE 3
Effects of caffeine on alleviating liver cirrhosis, different types of hepatitis, and HCC and its possible mechanisms. Caffeine attenuates BDL-induced liver cirrhosis in rats. Several clinical trials have shown the same result, and the mechanism may be related to the ability of caffeine to inhibit inflammation and angiogenesis. Viral assays have found that caffeine can inhibit HBV and HCV, while clinical trials have found that caffeine can alleviate hepatitis B, C, and AIH; its mechanism may be related to the inhibition of hepatitis virus replication and regulation of immune function. Recent preclinical studies and multiple clinical trials have found that caffeine attenuates HCC. Caffeine inhibits the proliferation of various HCC cells and attenuates chemical toxicant (TAA, DEN, and CCl4)-induced HCC and xenograft HCC in nude mice. Large clinical trials initiated in several countries have found that the risk of HCC is reduced in people with an oral coffee consumption habit; this may be due to the ability of caffeine to inhibit HCC cell proliferation and oxidative DNA damage and reduce HCC cell DNA repair.
FIGURE 4
FIGURE 4
Toxicology or adverse reactions of caffeine. The adverse reactions of caffeine on the cardiovascular, nervous, and reproductive systems are serious. Although most of the adverse reactions disappear after discontinuing oral administration, the impact on the fetus is more serious, which requires expecting mothers to be vigilant. Therefore, an oral dose of coffee is not recommended for women who are trying to become pregnant or who are pregnant.
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