Abstract
We have found a novel metabolic pathway of arylethers, involving the cleavage of the oxygen-aromatic ring bond. When p-(p-nitrophenoxy)phenol was utilized as a substrate, cleaved products, p-nitrophenol and p-benzoquinone, were formed in two cytochrome P450 model systems, meso-tetraphenylporphinatoiron(III) chloride-NaBH4/O2 system and meso-tetrakis (2,6-difluorophenyl)porphinatoiron(III) chloride-m-chloroperoxybenzoic acid (mCPBA) system. Rat liver microsomes also catalyzed this reaction, which was inhibited by a cytochrome P450-specific inhibitor, and it was confirmed that this cleavage proceeded in vivo. Further, experiments using [18O]mCPBA and 18O2 proved that the cleavage reaction is accompanied with the ipso-substitution by the oxygen atom of the active species in both cytochrome P450 model system and cytochrome P450. When the microsomal reactions of p-(p-nitrophenoxy)phenol analogues which lack a hydroxy group, namely p-nitrophenoxybenzene, p-(p-nitrophenoxy) anisole, and p-(p-nitrophenoxy) toluene, were investigated, the cleavage reaction occurred via p-(p-nitrophenoxy)phenol in the cases of p-nitrophenoxybenzene and p-(p-nitrophenoxy)anisole, indicating that a hydroxy group at the p-position to the ether bond is necessary for this pathway. This metabolic pathway appears to be important, because a diarylether linkage, which is very stable and has generally been thought to resist metabolism, is cleaved and benzoquinone, a highly toxic metabolite, is formed.
| Original language | English |
|---|---|
| Pages (from-to) | 402-409 |
| Number of pages | 8 |
| Journal | Archives of Biochemistry and Biophysics |
| Volume | 310 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1994 May |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Biophysics
- Biochemistry
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Novel Metabolic Pathway of Arylethers by Cytochrome P450 : Cleavage of the Oxygen-Aromatic Ring Bond Accompanying ipso-Substitution by the Oxygen-Atom of the Active Species in Cytochrome P450 Models and Cytochrome P450. / Ohe, Tomoyuki; Mashino, Tadahiko; Hirobe, M.
In: Archives of Biochemistry and Biophysics, Vol. 310, No. 2, 05.1994, p. 402-409.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel Metabolic Pathway of Arylethers by Cytochrome P450
T2 - Cleavage of the Oxygen-Aromatic Ring Bond Accompanying ipso-Substitution by the Oxygen-Atom of the Active Species in Cytochrome P450 Models and Cytochrome P450
AU - Ohe, Tomoyuki
AU - Mashino, Tadahiko
AU - Hirobe, M.
PY - 1994/5
Y1 - 1994/5
N2 - We have found a novel metabolic pathway of arylethers, involving the cleavage of the oxygen-aromatic ring bond. When p-(p-nitrophenoxy)phenol was utilized as a substrate, cleaved products, p-nitrophenol and p-benzoquinone, were formed in two cytochrome P450 model systems, meso-tetraphenylporphinatoiron(III) chloride-NaBH4/O2 system and meso-tetrakis (2,6-difluorophenyl)porphinatoiron(III) chloride-m-chloroperoxybenzoic acid (mCPBA) system. Rat liver microsomes also catalyzed this reaction, which was inhibited by a cytochrome P450-specific inhibitor, and it was confirmed that this cleavage proceeded in vivo. Further, experiments using [18O]mCPBA and 18O2 proved that the cleavage reaction is accompanied with the ipso-substitution by the oxygen atom of the active species in both cytochrome P450 model system and cytochrome P450. When the microsomal reactions of p-(p-nitrophenoxy)phenol analogues which lack a hydroxy group, namely p-nitrophenoxybenzene, p-(p-nitrophenoxy) anisole, and p-(p-nitrophenoxy) toluene, were investigated, the cleavage reaction occurred via p-(p-nitrophenoxy)phenol in the cases of p-nitrophenoxybenzene and p-(p-nitrophenoxy)anisole, indicating that a hydroxy group at the p-position to the ether bond is necessary for this pathway. This metabolic pathway appears to be important, because a diarylether linkage, which is very stable and has generally been thought to resist metabolism, is cleaved and benzoquinone, a highly toxic metabolite, is formed.
AB - We have found a novel metabolic pathway of arylethers, involving the cleavage of the oxygen-aromatic ring bond. When p-(p-nitrophenoxy)phenol was utilized as a substrate, cleaved products, p-nitrophenol and p-benzoquinone, were formed in two cytochrome P450 model systems, meso-tetraphenylporphinatoiron(III) chloride-NaBH4/O2 system and meso-tetrakis (2,6-difluorophenyl)porphinatoiron(III) chloride-m-chloroperoxybenzoic acid (mCPBA) system. Rat liver microsomes also catalyzed this reaction, which was inhibited by a cytochrome P450-specific inhibitor, and it was confirmed that this cleavage proceeded in vivo. Further, experiments using [18O]mCPBA and 18O2 proved that the cleavage reaction is accompanied with the ipso-substitution by the oxygen atom of the active species in both cytochrome P450 model system and cytochrome P450. When the microsomal reactions of p-(p-nitrophenoxy)phenol analogues which lack a hydroxy group, namely p-nitrophenoxybenzene, p-(p-nitrophenoxy) anisole, and p-(p-nitrophenoxy) toluene, were investigated, the cleavage reaction occurred via p-(p-nitrophenoxy)phenol in the cases of p-nitrophenoxybenzene and p-(p-nitrophenoxy)anisole, indicating that a hydroxy group at the p-position to the ether bond is necessary for this pathway. This metabolic pathway appears to be important, because a diarylether linkage, which is very stable and has generally been thought to resist metabolism, is cleaved and benzoquinone, a highly toxic metabolite, is formed.
UR - http://www.scopus.com/inward/record.url?scp=0028352457&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028352457&partnerID=8YFLogxK
U2 - 10.1006/abbi.1994.1185
DO - 10.1006/abbi.1994.1185
M3 - Article
C2 - 8179325
AN - SCOPUS:0028352457
VL - 310
SP - 402
EP - 409
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
SN - 0003-9861
IS - 2
ER -