Impact of aerosols on liver xenobiotic metabolism: A comparison of two methods of exposure

Publication Date: 1 March 2022

Bovard, P. et al. (2022) Impact of aerosols on liver xenobiotic metabolism: A comparison of two methods of exposure. Toxicol In Vitro. 79, 105277. DOI:10.1016/j.tiv.2021.105277


Cigarette smoking significantly raises the risk of acquiring a variety of cancers including airway, pancreatic, liver, and lung cancer. There are more than 6000 compounds in cigarette smoke (CS) that belong to multiple chemical classes such as aromatic amines, aldehydes, and volatile organic hydrocarbons. CS is largely composed of polycyclic aromatic hydrocarbons, which has been associated with the induction of cytochrome P450 (CYP) enzymes. Since CS impacts xenobiotic metabolism, CYP enzyme bioavailability is altered in smokers versus nonsmokers, impacting their ability to metabolize certain drugs.

One method of evaluating the impact of CS uses in vitro aerosol testing, which comes with limitations because it inadequately recapitulates human physiology. With this method, it is also difficult to establish physiological exposure to complex mixtures in vitro. In this study, the researchers assessed the effects of CS and tobacco heating system (THS) aerosols on CYP functions using two methods of aerosol exposure: traditional aqueous fractions (AF) and a novel multi-organs-on-a-chip (MOC) system.   

The results disclosed within this study reveal that CS AF exposure led to a dose-dependent increase in the activities of CYP1A1/1B1, CYP1A2, and CYP2B6 and a decrease in CYP2C9, CYP2D6, and CYP3A4 enzyme activities in liver spheroids. On the contrary, the effect of THS AF exposure on liver spheroid CYP enzyme activity were 8 times lower for all enzymes tested compared to those subjected to CS AF. Researchers also implemented the use of an MOC system, co-culturing liver spheroids with bronchial tissues, to create a more physiologically relevant aerosol exposure system. Using the MOC system, the study demonstrated a robust effect on liver xenobiotic metabolism, especially with repeated CS exposure. Repeated CS aerosol exposure of the bronchial tissues induced CYP1A1/1B1 and CYP1A2 enzyme activities in both the liver spheroids and bronchial tissues. Additionally, liver spheroids exhibited an increase in CYP3A4 activity and no change in CYP2C9 or CYP2D6 activity with repeated CS exposure, which is reminiscent of effects observed in smokers. The effects of CYP activity in bronchial and liver tissues following repeated THS exposure were smaller than those noted during repeated CS exposure, even at doses over 4 times higher than administered with CS. In conclusion, this study demonstrates that both CS and THS aerosols affect liver xenobiotic metabolism, however, CS aerosols make a more pronounced impact. Furthermore, this research emphasizes the importance of using physiologically relevant systems like the MOC for their ability to mimic in vivo conditions and provide results that more closely mirror trends found in the clinic.

Keywords: Multi-organs-on-a-chip, organ-on-a-chip, aerosol, xenobiotic metabolism, cigarette smoke, aqueous fraction, liver, lungs, CYP enzymes