Industrial, Biocide, and Cosmetic Chemical Inducers of Cholestasis

Abstract

A frequent side effect of many drugs includes the occurrence of cholestatic liver toxicity. Over the past couple of decades, drug-induced cholestasis has gained considerable attention, resulting in a plethora of data regarding its prevalence and mechanistic basis. Likewise, several food additives and dietary supplements have been reported to cause cholestatic liver insults in the past few years. The induction of cholestatic hepatotoxicity by other types of chemicals, in particular synthetic compounds, such as industrial chemicals, biocides and cosmetic ingredients, has been much less documented. Such information can be found in occasional clinical case reports of accidental intake or suicide attempts as well as in basic and translational study reports on mechanisms or testing of new therapeutics in cholestatic animal models. This paper focuses on such non-pharmaceutical and non-dietary synthetic chemical inducers of cholestatic liver injury, in particular alphanaphthylisocyanate, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, methylenedianiline, paraquat, tartrazine, triclosan, 2-octynoic acid and 2-nonynoic acid. Most of these cholestatic compounds act by similar mechanisms. This could open perspectives for the prediction of cholestatic potential of chemicals.

Rodent models of cholestatic liver disease: A practical guide for translational research

“…α‐naphtylisothiocyanate (ANIT) is a chemical used for preparation of cationic aromatic urethane 137 . The compound is also well known among researchers for adequately inducing cholestasis in rats and mice, 79,171 by specifically targeting bile duct epithelial cells followed by hepatocellular necrosis 137,172 . Chronic and recurrent exposure to ANIT via the diet resembles an experimental setting of chronic cholangitis, bile duct hyperplasia and peribiliary fibrosis 172‐174 .…”

Screening of repeated dose toxicity data in safety evaluation reports of cosmetic ingredients issued by the Scientific Committee on Consumer Safety between 2009 and 2019

“…It is well known that drug-induced liver injury remains a common cause of the withdrawal of drugs in pre-clinical and even clinical phases of drug development (Lee 2013;Onakpoya et al, 2019). It has also been reported that chemicals from various other application areas could trigger liver adversities such as steatosis and cholestasis (Al-Eryani et al 2015;Vilas-Boas et al 2019). Here, for cosmetic ingredients, certain combinations of changes in relevant parameters that could indicate liver steatosis and cholestasis were collected (Tables 2 and 3) for all potentially liver-affecting compounds (49).…”

Dataset on transcriptomic profiling of cholestatic liver injury induced by food additives and a cosmetic ingredient

“…A total of 3 different batches of HepaRG cells were exposed to 3 non-pharmaceutical compounds, namely the food additives SUN (10 mM) and TART (50 mM) and cosmetic ingredient TRI (0.050 mM), which were believed to bear a cholestatic risk [ 2 , 3 ], in the presence of a 50 × concentrated BA mixture ( i.e. datasets SUNSET + BA 1-3; TART + BA 1-3 and TRI + BA 1-3).…”