It is a secondary metabolite produced by fungi that contaminates long-stored food and it can cause a variety of toxic effects, including kidney, liver and cell damage.

Citrinin is mainly found in stored grains, but sometimes also in fruits and other plant products.

[3] In 1993 the World Health Organisation International Agency for Research on Cancer started to evaluate the carcinogenic potential of mycotoxins.

The health hazards of mycotoxins to humans or animals have been reviewed extensively in recent years.

[8] As stated above, citrinin decomposes at temperatures higher than 175 °C, providing that it is under dry conditions.

[10] Citrinin often occurs together with other mycotoxins like ochratoxin A or aflatoxin B1, because they are produced by the same fungi species.

The nephrotoxic effects of ochratoxin A and citrinin, for example, are increased synergistic when exposure to both takes place.

[11] Next to that, the co-exposure of these compounds is expected to be involved in the pathogenesis of a human kidney disease, called Balkan Endemic Nephropathy.

Because of this and the fact that people in general have a high consumption of cereal-based foods, the Panel on Contaminants in the Food Chain (the CONTAM Panel) considered that grains might be the major contributor of dietary exposure to citrinin.

The CONTAM Panel concluded that not enough data were available in the literature to carry out a dietary exposure assessment.

The acute toxicity of citrinin depends on the route of administration and on the species used for the research.

Mrl2 encodes a non heme Fe(II) dependent oxygenase (CitB) which is involved in ring expansion.

CitB oxidizes the C-atom of a methyl group bound to the aromatic ring and produces an alcohol.

Then CitD converts it into a carboxylic acid, via a thiohemiacetal intermediate which rises as a result of the transfer of hydride from NADPH.

[1] Aspergillus oryzae has been transformed to efficiently industrially produce citrinin, which is not normally one of its SMs.

[18][19] Various in vitro studies have revealed the involvement of citrinin toxicity in reduced cytokine production, inhibition of RNA and DNA synthesis, induction of oxidative stress, inhibition of nitride oxide gene expression, increase in ROS production and activation of apoptotic cell death via signal transduction pathways and the caspase-cascade system.

[8] Johannessen et al. (2007) investigated the production of cytokine and cell viability in response to citrinin treatment.

[20][21] Moreover, Huang found that JNK and PAK2 (both associated with apoptosis) were activated in a dose-dependent manner after CTN treatment of osteoblasts.

These results suggest that ROS is an upstream activator of JNK and can possibly control caspase-3 to trigger apoptosis when treated with CTN.

[23] It has been found that endotoxin LPS and inflammatory mediators as IFN-γ, TNF-α and IL-1β can induce iNOS (NO synthesis enzyme) gene expression by activating transcription factors including NF-κB and STAT1a.

CTN also reduced STAT-1a phosphorylation and IRF-1 (a transcription factor that is targeted by STAT-1a and can bind to the IRE of the iNOS gene) mRNA levels.

These results suggest that CTN inhibits iNOS gene expression through suppression of NF-κB by blocking IκB-α phosphorylation.

From plasma concentrations it could be concluded that radioactivity rapidly disappeared after 12 hours and eventually only 0.9% was left.

Therefore, the presence of 6.8% radioactivity in the gastrointestinal tract after 30 minutes probably reflected the secreted label by the liver and underwent enterohepatic circulation before ending up in the intestine.

In comparison with male rats, two metabolites were found in urine, plasma, and bile with similar retention times and more polar appearance than the parent compound.

[24] A recent study of Ali et al. (2015) investigated the levels of citrinin (CTN) and its human metabolite dihydrocitrinone (HO-CTN) in urine samples of 50 healthy adults (27 females and 23 males).

Based on the report of the European Food Safety Authority, the critical citrinin concentration from children (up to 3–9 years old) is 53 μg/kg of grains and grain-based products while 19 to 100 μg/kg is for adults.

Unfortunately, there is no firm conclusion for the exact citrinin concentration that can cause nephrotoxicity for long periods of consumption.

[26] Recent studies show that the mitochondria respiratory system is another target of citrinin.

It is observed that after administration of 20 and 40 mg citrinin/kg bodyweight, pigs suffer from growth depression, weight loss and glycosuria and decreasing β-globulin after 3 days.