Contribution of methylsulfonyl metabolites of m-dichlorobenzene to the heme metabolic enzyme induction by the parent compound in rat liver.
In the present study, we investigated the contribution of methylsulfonyl metabolites derived from m-dichlorobenzene (m-DCB) on the heme metabolic enzyme induction by the parent compound in rats. The time courses of the effects of a single ip administration of m-DCB (200 mg/kg, 1.36 mmol/kg) and 2,4- and 3,5-dichlorophenyl methyl sulfones (2,4- and 3,5-DCPSO2Mes) (each 50 mumol/kg) on hepatic microsomal cytochrome P450 content were almost in parallel with those on the total heme content in liver microsomes. m-DCB significantly increased the heme oxygenase activity, but 2,4- and 3,5-DCPSO2Mes did not. On the other hand, m-DCB and both methyl sulfones markedly enhanced the delta-aminolevulinic acid (ALA) synthetase activity. No change was observed in percentage saturation of the tryptophan pyrrolase activity after administration of m-DCB, whereas this ratio at 6 hr after injection of 3,5-DCPSO2Me was increased. In the liver of the DL-buthionine-(S,R)-sulfoximine (BSO)-treated rats dosed with m-DCB, both of 2,4- and 3,5-DCPSO2Mes were present at significantly lower concentrations than in non-BSO-treated rats. Additionally, the m-DCB did not elevate the ALA synthetase activity in the BSO-treated rat. On the other hand, the administration of either 2,4- or 3,5-DCPSO2Mes to BSO-treated rats resulted in induction of ALA synthetase. m-DCB and 2,4- and 3,5-DCPSO2Mes produced a dose-related increase in liver levels of methyl sulfones. The changes in the ALA synthetase activity after the administration of varying doses of m-DCB were similar to those after the administration of 2,4- or 3,5-DCPSO2Mes, whereas the sum of the concentration of two methyl sulfones in the liver of rats dosed with m-DCB was almost the same as the concentration of methyl sulfone after the administration of either 2,4- or 3,5-DCPSO2Mes. The results strongly suggest that the methyl sulfones derived from m-DCB, i.e., 2,4- and 3,5-DCPSO2Mes, contribute highly to the induction of the ALA synthetase activity by the parent compound.
Kato
Y
Y
School of Pharmaceutical Science, University of Shizuoka, Japan.
Kogure
T
T
Sato
M
M
Kimura
R
R
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis; D000818:Animals; D019328:Buthionine Sulfoximine; D002722:Chlorobenzenes / Q000378:metabolism* / Q000494:pharmacology; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013450:Sulfones / Q000494:pharmacology*; D014366:Tryptophan Oxygenase / Q000096:biosynthesis
D002722:Chlorobenzenes; D013450:Sulfones; D008717:Methionine Sulfoximine; D006418:Heme; D019328:Buthionine Sulfoximine; C042146:1,3-dichlorobenzene; C025910:dimethyl sulfone; D014366:Tryptophan Oxygenase; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D004121:Dimethyl Sulfoxide