Effect of regular organic solvents on cytochrome P450-mediated metabolic activities in rat liver microsomes.
The effects of regular organic solvents on the metabolic activities of various human cytochromes P450 (P450s) have been reported. However, very little is known about their influence on metabolic activities mediated by P450s in the rat liver microsomes (RLM). The purpose of this study was to investigate the effects of organic solvents such as methanol, acetonitrile, dimethyl sulfoxide (DMSO), acetone, and ethanol on CYP1A, CYP2C, CYP2D, CYP2E, and CYP3A-mediated metabolism using RLM. The results showed that the activities of most rat P450 enzymes appeared to be organic solvent-dependent, and the metabolism of the tested probes were remarkably reduced when the concentration of organic solvents was up to 5% v/v, whereas most organic solvents demonstrated no significant interference when the concentration was below 1%, with the exception of DMSO. In addition, organic solvents exhibited different inhibitory effects, for example, CYP2D and CYP2E showed a significant reduction of activities at lower concentrations of organic solvents. Hence, this phenomenon should be taken into consideration when designing in vitro metabolism studies of new chemical entities. Therefore, we recommend acetonitrile as the most suitable solvent for RLM incubations, and the content of organic solvent should be kept lower than 1% v/v.
Li
Dan
D
Department of Pharmacy, 6th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
Han
Yonglong
Y
Meng
Xiangle
X
Sun
Xipeng
X
Yu
Qi
Q
Li
Yan
Y
Wan
Lili
L
Huo
Yan
Y
Guo
Cheng
C
D000096:Acetone / Q000494:pharmacology; D000097:Acetonitriles / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D000432:Methanol / Q000494:pharmacology; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000494:pharmacology*
D000097:Acetonitriles; D012997:Solvents; D000096:Acetone; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D000432:Methanol; D004121:Dimethyl Sulfoxide; C032159:acetonitrile