Introduction

Caffeine and caffeic acid are two bioactive compounds present in plant foods and are major constituent of coffee, cocoa, tea, cola drinks and chocolate. Although not structurally related, caffeine and caffeic acid have been reported to elicit neuroprotective properties.

Biological activity

Caffeic acid (C9H8O4; 3,4-dihydroxycinnamic acid) is an orally bioavailable, hydroxycinnamic acid derivative and a polyphenol, with antioxidant, anti-inflammatory, and antineoplastic properties. Caffeic acid prevents oxidative stress, thereby preventing DNA damage induced by free radicals. In plants, it inhibits EC 1.13.11.33: arachidonate 15-lipoxygenase, EC 2.5.1.18: glutathione transferase, EC 1.13.11.34: arachidonate 5-lipoxygenase, and EC 3.5.1.98: histone deacetylase.

Caffeic acid targets and inhibits the histone demethylase (HDM) oncoprotein gene amplified in squamous cell carcinoma 1 (GASC1; JMJD2C; KDM4C), inhibiting cancer cell proliferation. GASC1, a member of the KDM4 subgroup of Jumonji (Jmj) domain-containing proteins, demethylates trimethylated lysine 9 and lysine 36 on histone H3 (H3K9 and H3K36) and plays a key role in tumour cell development.

In hepatocarcinomas, caffeic acid suppresses the expression of MMP-2 and MMP-9 (metalloproteases 2 and 9). It has been demonstrated that caffeic acid inhibits MMP-2 and MMP-9 by inhibiting NF-kB activation, as demonstrated in liver cancer cells stimulated by PMA (activating protein 1), which decreases tumour growth and invasion.

Toxicity

Caffeic acid was studied in mice with F0 females and their F1 offspring to determine its reproductive and developmental Toxicity. In a three-segment study, female F0 mice were continuously exposed to 0, 0.15, 5, or 150 mg/kg/day of caffeic acid by gavage. The administration of 5 and 150 mg/kg/day of caffeic acid before gestation day 6 adversely affected embryo implantation. The weight gain of the fetus was also affected by caffeic acid of 150 mg/kg/day. There was no evidence of maternal Toxicity, fetal teratogenesis, or post-natal effects on pup development.

Those who suffer from insomnia may find that caffeic acid has a mild stimulant effect that can worsen the condition. However, this effect is much less than that of caffeine. No data is available on the carcinogenicity of caffeic acid in humans, but there is sufficient evidence that it is carcinogenic in experimental animals. The IARC evaluates caffeic acid as a possible human Group 2B carcinogen.

The carcinogenic potential of caffeine was tested by administering it orally to mice and rats. In mice, it caused renal-cell adenomas in females as well as renal tubular-cell hyperplasia in both sexes. It was observed that male mice developed an increased incidence of both squamous-cell papillomas and carcinomas of the forestomach and a high incidence of hyperplasia of the forestomach. It produced squamous-cell papillomas and carcinomas in the forestomach in rats of both sexes, as well as a few renal-cell adenomas in males.

LD50 dose in mice is >721 mg/kg (via intraperitoneally). It can cause epithelial hyperplasia in the forestomach of rats when given 20 g/kg mixed in diet for 4 weeks. It is a GI and kidney irritant.

References

[1] S.F. Akomolafe . “Effect of caffeine, caffeic acid and their various combinations on enzymes of cholinergic, monoaminergic and purinergic systems critical to neurodegeneration in rat brain—In vitro.” Neurotoxicology 62 (2017): Pages 6-13.

[2] Caffeic Acid - an overview | ScienceDirect Topics https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/caffeic-acid