Thyrotoxic rubber antioxidants, 2-mercaptobenzimidazole and its methyl derivatives, cause both inhibition and induction of drug-metabolizing activity in rat liver microsomes after repeated oral administration
| Autor: | Makoto Usami, Tomohiko Irie, Yasuo Ohno, Atsuko Miyajima, Katsuyoshi Mitsunaga, Kazue Sakemi-Hoshikawa, Momoko Sunouchi |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Biophysics Administration Oral Flavin-containing monooxygenase Pharmacology Reductase Biochemistry Antioxidants Mixed Function Oxygenases Structure-Activity Relationship 03 medical and health sciences Cytochrome P-450 Enzyme System Oral administration Animals Toxicokinetics Rats Wistar Enzyme inducer Molecular Biology Dose-Response Relationship Drug 030102 biochemistry & molecular biology biology Chemistry Cytochrome P450 Organ Size Cell Biology Monooxygenase Rats 030104 developmental biology Liver Enzyme Induction Toxicity Microsomes Liver biology.protein Benzimidazoles |
| Zdroj: | Biochemical and Biophysical Research Communications. 492:116-120 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2017.08.024 |
| Popis: | We examined the effects of thyrotoxic rubber antioxidants, 2-mercaptobenzimidazole (MBI, 0.3 mmol/kg/day) and its methyl derivatives, methyl-MBIs [4-methyl-MBI (4-MeMBI, 0.6 mmol/kg/day), 5-methyl-MBI (5-MeMBI, 0.6 mmol/kg/day), and 4(or 5)-methyl-MBI (4(5)-MeMBI, 0.6 or 1.2 mmol/kg/day)], on the drug-metabolizing activity in male rat liver microsomes by 8-day repeated oral administration. The weight of liver and thyroid were increased by all the test chemicals; MBI was most potent, and there was no additive or synergistic effect between 4-MeMBI and 5-MeMBI. MBI decreased the cytochrome P450 (CYP) content, NADPH-cytochrome P450 reductase (POR) activity, 7-ethoxycoumarin O-deethylation (ECOD) activity, and flavin-containing monooxygenase (FMO) activity, but increased the 7-pentoxyresorufin O-depentylation (PROD) activity, suggesting inhibition of the drug-metabolizing activity on the whole but induce some activities such as the CYP2B activity. On the contrary, all the methyl-MBIs increased the CYP content, CYB5 content, ECOD activity, 7-ethoxyresorufin O-deethylation (EROD) activity, and PROD activity, indicating that they are mostly inducible of the CYP activity. However, the methyl-MBIs decreased the FMO activity, and 5-MeMBI and 4(5)-MeMBI appeared inhibitory for CYPs 2C11 and 2C13. Between 4-MeMBI and 5-MeMBI, there was no additive or synergistic effect on the drug-metabolizing activity, but was counteraction. It was concluded that MBI and methyl-MBIs had both inhibitory and inducible effects on the drug-metabolizing activity in rat liver microsomes at thyrotoxic doses. The effects of 4(5)-MeMBI indicated that the increased liver weight alone can be a hepatotoxic sign but not an adaptive no-adverse response in toxicity studies. The present results were related to the toxicokinetic profiles of MBI and 4(5)-MeMBI in the repeated toxicity studies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect