Toshiro Murata

Gastrointestinal absorption of inorganic mercuric compounds in vivo and in situ

The absorption of inorganic mercury in rats was studied by using ligated gastrointestinal segments and perfusion of small intestine. Poorly soluble mercuric oxide (HgO) as well as mercuric chloride (HgCl2) was absorbed from the ligated segments in the following order: duodenum greater than stomach = jejunum = ileum. The ligation of bile duct decreased the duodenal absorption of HgCl2, while no change was observed in that of HgO. In the bile duct-ligated rats, the coadministration of bile increased the absorption of HgCl2 compared to that in rats without the ligation. The absorption of HgCl2 was increased with an increase of pH of the solution perfused into small intestine. These results suggest that the alkalinity of bile promotes the absorption of HgCl2.

Evidence that methylsulfonyl metabolites of m-dichlorobenzene are causative substances of induction of hepatic microsomal drug-metabolizing enzymes by the parent compound in rats

This study was undertaken to clarify the relationship between the formation of 2,4- and 3,5-dichlorophenyl methyl sulfones, metabolites of m-dichlorobenzene (DCB), and their inducing effect on hepatic microsomal drug-metabolizing enzymes in rats. When m-DCB was injected ip into bile duct-cannulated rats, little or no methyl sulfones were detected in blood, liver, kidneys, adipose tissue, or bile. In the antibiotic-pretreated rats dosed with m-DCB, metabolite concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from m-DCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of m-DCB administration on the activities of aminopyrine and aniline metabolizing enzymes and the contents of cytochromes P-450 and b5 in hepatic microsomes were scarcely observed in the bile duct-cannulated and antibiotic-pretreated rats, in which the drug-metabolizing enzymes were able to be induced by phenobarbital treatment. On the other hand, in rats administered 2,4- or 3,5-dichlorophenyl methyl sulfone hepatic distribution of each methyl sulfone was similar to that in intact rats, and the degree of increase of the above four parameters was nearly the same as that in the intact rats. These findings provide evidence that the induction of drug-metabolizing enzymes by m-DCB is not due to the action of m-DCB but is due to its methylsulfonyl metabolites.

Gastrointestinal absorption of inorganic mercuric compounds in vitro

Effects of intraluminal pH on the intestinal absorption and tissue binding of HgCl2 and HgO were studied in the everted sac of rat small intestine. The sac was incubated in media containing HgCl2 or HgO (10(-5 M] at different pH values. With an increase in pH, the uptake of HgCl2 in the intestinal tissue decreased and the transport of HgCl2 through the tissue increased. Similar pH dependence was observed in the uptake of HgO. The transport of HgCl2 seemed to be correlated with mercury bound to a protein (molecular weight between 440,000 and 669,000) and to be inversely correlated with that bound to intestinal metallothionein. These results suggest that the increase of intraluminal pH promotes the absorption of HgCl2 accompanied by a change in the binding of HgCl2 to the everted tissue sac.

Induction of hepatic microsomal drug-metabolizing enzymes by sulfur-containing metabolites of chlorinated benzenes in rats

3,5-Dichlorophenyl methyl sulfide and its oxidized compounds, metabolites of m-dichlorobenzene, increased the activity of aniline hydroxylase and aminopyrine N-demethylase and the content of cytochromes P-450 and b5 in rat liver microsomes. Hexobarbital sleeping time was reduced by these three compounds. After the administration of the sulfide to rats, 3,5-dichlorophenyl methyl sulfone appeared in blood, liver, and kidneys, and remained detectable in the blood and the tissues between 120 and 240 hr. The sulfone was considered to play a principal role in the induction by these compounds. Other chlorophenyl methyl sulfones also showed similar induction activity.