Abstract
Cytochrome P-450 (CYP) 3A2 and CYP2C11 are sources of 70 and 30%, respectively, of N-vinylprotoporphyrin IX (N-vinylPP) formation after administration of 3-[(arylthio)ethyl]sydnone (TTMS) to rats. Female rats receiving TTMS were pretreated with dexamethasone, which induces CYP3A1 preferentially to CYP3A2. The resulting 12-fold increase in N-vinylPP formation showed that CYP3A1 was also a source ofN-vinylPP. Phenobarbital (PB) pretreatment, which induces CYP2B1/2 and 3A1/2 in male rats, increasedN-vinylPP formation after TTMS administration. Troleandomycin, a selective CYP3A inhibitor, was unable to decrease TTMS-mediated N-vinylPP formation in PB-treated male rats, indicating that CYP2B1/2 were sources ofN-vinylPP. This conclusion was supported by demonstrating a 15-fold increase in TTMSinducedN-vinylPP formation in female rats after CYP2B1/2 induction with PB pretreatment. Allylispropylacetamide (AIA) inactivates rat CYP2B1/2, 2C6, 2C7, 2C11, and 3A1/2. Troleandomycin was unable to decrease N-AIA protoporphyrin IX adduct (N-AIAPP) formation, showing that CYP3A1/2 were not susceptible to AIA-mediated N-alkylation.N-AIAPP formation in females was approximately 30% of that in males, and thus we attribute 30% of N-AIAPP formation in males to the non-gender-specific isozymes (CYP2C6, 2C7, and/or 2B1/2), whereas approximately 70% originates from CYP2C11. PB treatment in female rats resulted in a 5-fold increase inN-AIAPP formation, showing that CYP2B1/2 were also susceptible to N-alkylation mediated by AIA. 1-Aminobenzotriazole elicited formation of equivalent amounts ofN′N-aryl bridged protoporphyrin IX in male and female rat liver, demonstrating that nonselective mechanism-based inactivation is accompanied by nonselective conversion of the CYP heme moieties to N′N-aryl bridged protoporphyrin IX.
Footnotes
-
Send reprint requests to: Gerald S. Marks, Ph.D., Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail:gsm{at}post.queensu.ca
-
This research was supported by the Medical Research Council of Canada.
- Abbreviations used are::
- N-alkylPP
- N-alkylprotoporphyrin IX
- N-vinylPP
- N-vinylprotoporphyrin IX
- N-ethylPP
- N-ethylprotoporphyrin IX
- 4-ethylDDC
- 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine
- TTMS
- 3-[(arylthio)ethyl]sydnone
- CYP
- cytochrome P-450
- PB
- phenobarbital
- DEX
- dexamethasone
- TAO
- troleandomycin
- ABT
- 1-aminobenzotriazole
- AIA
- allylisopropylacetamide
- N-AIAPP
- N-allyisopropylacetamide protoporphyrin IX (adduct)
- NNAPP
- N′N-aryl bridged protoporphyrin IX
- ERND
- erythromycin N-demethylase
- Received December 21, 1998.
- Accepted April 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
Log in using your username and password
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.