Investigation Of The Absorption,Metabolism And Toxic Effects Of The Non-planar Polycyclic Aromatic Hydrocarbons: Corannulene

Corannulene(COR),a non-planar polycyclic aromatic hydrocarbon(PAH),has a bowl-shape structure.Due to their unique structures and properties,COR and its derivatives have been applied in various fields including drug carrier,disease diagnosis and healthcare.This has raised a great concern about their potential bioactivity and toxicity.However,very limited study has been undertaken to evaluate their biological effects.In the present study,the absorption,tissue distribution,metabolism and toxic effects of COR were investigated in vitro and in vivo by comparing with benzo[?]pyrene(BaP),a typical model PAH with planar structure.Compared to BaP,COR showed slower absorption and metabolism both in vitro and in vivo,but no difference in the metabolic patterns and rates in liver microsomes when compared with BaP.Further analysis revealed both COR and BaP were metabolized majorly by cytochrome P450 1(CYP1)isozymes.The results of q RT-PCR and western blot demonstrated that the inducibility of COR on CYP1 m RNA and protein expression was poorer than that of BaP,leading to a slower metabolism of COR.Interestingly,both COR and BaP could enhance the nuclear translocation of aryl hydrocarbon receptor(AHR),the key regulator protein of CYP1.Knockdown of AHR by si RNA attenuated the induction of CYP1 by both COR and BaP in hepatocytes,suggesting that COR is a weak activator of AHR.Both in vitro and in vivo findings showed that COR is less toxic than BaP.Derivatization greatly influenced the cytotoxicity of COR,which was positively correlated with their binding affinities to AHR and inductive effects on CYP1.COR had little effect on the body weights and major metabolic pathways of mice,which was consistent with its poor activation of on AHR and CYP1.RNA-seq analysis revealed that COR caused less effect on liver transcriptomes than BaP,however,both COR and BaP significantly altered the m RNA expressions of genes involved in carcinogenicity,oxidative stress,immune response and rhythm regulation.Additionally,COR elicited oxidative stress and microbiota alterations in the intestine of mice.These results indicate that the metabolic activation by AHR-mediated induction of CYP1 is involved in the toxic effects of COR.In summary,the present study demonstrates: 1)COR can be metabolized by CYP1isozymes;2)COR toxicity is dependent on AHR;3)Derivatization greatly influences the cytotoxicity of COR,which was positively correlated with their binding affinities to AHR;4)COR shows potential effects on carcinogenicity,oxidative stress,immune response and rhythm regulation;5)COR elicites oxidative stress and alters microbiota composition in the intestine of mice.These findings are important to understand the biological and toxic properties of COR,and will provide a basis of the future safety evaluations of COR and its relative materials.