Contribution of methylsulfonyl metabolites of m-dichlorobenzene to the heme metabolic enzyme induction by the parent compound in rat liver

Toxicol Appl Pharmacol. 1988 Dec;96(3):550-9. doi: 10.1016/0041-008x(88)90014-2.

Abstract

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.

MeSH terms

  • 5-Aminolevulinate Synthetase / biosynthesis
  • Animals
  • Buthionine Sulfoximine
  • Chlorobenzenes / metabolism*
  • Chlorobenzenes / pharmacology
  • Dimethyl Sulfoxide
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Heme / metabolism*
  • Heme Oxygenase (Decyclizing) / biosynthesis
  • Liver / enzymology*
  • Male
  • Methionine Sulfoximine / analogs & derivatives
  • Methionine Sulfoximine / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Sulfones / pharmacology*
  • Tryptophan Oxygenase / biosynthesis

Substances

  • Chlorobenzenes
  • Sulfones
  • Methionine Sulfoximine
  • Heme
  • Buthionine Sulfoximine
  • 1,3-dichlorobenzene
  • dimethyl sulfone
  • Tryptophan Oxygenase
  • Heme Oxygenase (Decyclizing)
  • 5-Aminolevulinate Synthetase
  • Dimethyl Sulfoxide