Effects of Methoxychlor and 2,2-bis (<b><i>p</i></b>-Hydroxyphenyl)-1,1,1-Trichloroethane on Cytochrome P450 Enzyme Activities in Human and Rat Livers

Abstract

Cytochrome P450 (CYP) enzymes are involved in the metabolism of endogenous and exogenous compounds. Human and rat liver microsomes were used to investigate the inhibitory effects of methoxychlor (MXC) and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on the activities of corresponding human and rat CYPs. Probe drugs were used to test the inhibitory effects of MXC and HPTE on human and rat CYPs. The results showed that MXC and HPTE inhibited both human CYP2C9 and rat liver CYP2C11 activity, with half-maximal inhibitory concentration (IC₅₀) values of 15.47 ± 0.36 (MXC) and 8.87 ± 0.53 μmol/l (HPTE) for human CYP2C9, and of 22.45 ± 1.48 (MXC) and 24.63 ± 1.35 μmol/l (HPTE) for rat CYP2C11. MXC and HPTE had no effects on human CYP2C19 activity but inhibited rat CYP2C6 activity with IC₅₀ values of 14.84 ± 0.04 (MXC) and 8.72 ± 0.25 μmol/l (HPTE). With regard to human CYP2D6 and rat CYP2D2 activity, only HPTE potently inhibited human CYP2D6 activity, with an IC₅₀ value of 16.56 ± 0.69 μmol/l. Both chemicals had no effect on human CYP3A4 and rat CYP3A1 activity. In summary, MXC and HPTE are potent inhibitors of some human and rat CYPs.

Development of an alternative zebrafish model for drug‐induced intestinal toxicity

“…CYP3A4 is known to be importantly expressed in the human small intestines and liver, although zebrafish and rats do not have the same exact CYP3A isoform as humans do. Only zebrafish CYP3A65 (Goldstone et al, ) and rat CYP3A1 (Chen et al, ) are highly expressed in their intestines and liver, respectively, similar to the expression of human CYP3A4. Moreover, zebrafish CYP3A65 has been known to share synteny with human CYP3A‐se1, −se2 and is 54% identical to human CYP3A4 (Tseng et al, ; Verstraelen et al, ).…”

“…Moreover, because of ethical concerns, alternative methods aiming to reduce rodent experiments are being recommended globally (Doke & Dhawale, ; Rollin, ; Zurlo, Rudacille, & Goldberg, ). In addition, it has been proved that rat CYP3A1, which is most abundantly expressed in the liver and the gastrointestinal tract like human CYP3A4, has only a limited similarity with human CYP3A4 and this validates the limitations of rats as an intestinal toxicity model (Chen, Pan, Wang, Chen et al, ; Ohkura et al, ; Videau et al, ). To overcome the differences between humans and laboratory animals, alternative methods using human cell lines have been developed.…”

Protective effects of baicalin on diethyl nitrosamine‐induced liver cirrhosis by suppressing oxidative stress and inflammation

“…All these proteins play essential roles in lipid metabolism and antioxidant stress (Vilaseca et al., 2017). However, the disparity can be observed between the microsomal models of these two species (Abdullah & Ismail, 2018), as supported by the research that human liver microsomes possess stronger drug metabolism and cytotoxic metabolism capabilities compared to rat liver microsomes, therefore making them susceptible to drug induction or inhibition (B. Chen et al., 2015). Therefore, a discrepancy may be inevitable in an attempt to interpret the effects of BA on the levels of liver function‐related biochemical indexes, oxidative stress‐related indexes, and inflammatory factors in the serum of cirrhosis model rats or diseased human liver, which should be demonstrated by performing further clinical trials.…”