Shinichi Yoshihara

Inductive effect on hepatic enzymes and acute toxicity of individual polychlorinated dibenzofuran congeners in rats

Abstract Toxicological assessment of 13 individual polychlorinated dibenzofurans (PCDFs) with varying chlorine substitutions was made in young male Wistar rats. All the 9 congeners having at least three chlorine atoms in the ring positions at 2, 3, 7 and 8, such as 1,2,7,8-, 2,3,6,7-, and 2,3,7,8-tetrachlorodibenzofurans (TCDFs), 1,2,3,7,8-, 1,2,6,7,8-, 2,3,4,7,8-pentachlorodibenzofurans (PenCDFs), 1,2,3,4,6,7- and 1,2,3,4,7,8-hexachlorodibenzofurans (HCDFs), exhibited a typical 3-methylcholanthrene (MC)-type induction, i.e., a marked increase in activity of aryl hydrocarbon hydroxylase (AHH) and DT-diaphorase in the liver. The most potent congeners were 2,3,7,8-TCDF and 2,3,4,7,8-PenCDF, both of which significantly induced the AHH and DT-diaphorase even at a single dose of 1 μg/kg. On the contrary, the congeners having two or less chlorine atoms in the lateral ring positions, such as 2,8-dichlorodibenzofuran, 1,3,6,7- and 1,3,6,8-TCDFs, and 1,2,4,6,8-PenCDF, did not show any inductive effect on these hepatic enzymes at the single dose of 5 or 10 mg/kg. All the MC-type PCDFs except for 1,2,7,8-TCDF caused a marked atrophy of the thymus and a hypertrophy of the liver in rats, while no toxic signs were observed in animals treated with the congeners lacking the MC-type inducing ability. The ranking of toxic potencies of the MC-type PCDFs coincided well with their inducing abilities. The hepatic disposition of the congeners varied markedly. For example, 2,3,7,8-TCDF and 2,3,4,7,8-PenCDF showed an equipotent toxicity, however, the hepatic concentration of PenCDF was about 20-fold higher than that of TCDF. These results clearly indicate that the acute toxicity of PCDF congeners is well correlated with their MC-type inducibility, but not with their hepatic distribution.

Accumulation of polychlorinated dibenzofurans in the livers of monkeys and rats.

Abstract A mixture of polychlorinated dibenzofurans (PCDFs) was analysed by gas chromatography, mass fragmentography and high-pressure liquid chromatography. The mixture consisted of 14% 1,2,7,8-tetra-chlorodibenzofuran (1,2,7,8-tetra-CDF), 35% 2,3,7,8-tetra-, 1% 1,2,4,7,8-penta-, 49% 1,2,3,7,8-penta-, 1% 2,3,4,7,8-penta- and 1% hexa-CDF. The mixture was administered orally to monkeys and ip to rats. The livers of the animals were analysed for the individual PCDFs. It was found that the accumulative properties of the different PCDFs varied. 2,3,4,7,8-Penta-CDF was the most highly accumulative in the livers of both species.

3,4,5,3′,4′-Pentachlorobiphenyl as a useful inducer for purification of rat liver microsomal cytochrome P448

Abstract An easy purification of rat liver microsomal cytochrome P448 was performed by using 3,4,5,3′,4′-pentachlorobiphenyl as an inducer. The cytochrome P448, a high spin form, was purified to 18.1 nmoles/mg protein with a good yield by ω-aminooctyl Sepharose 4B column chromatography followed by a hydroxyapatite column chromatography. This hemoprotein cross-reacted with antibody to cytochrome P448 from β-naphthoflavone-treated rats, but not with antibody to cytochrome P450 from phenobarbital-treated rats at all. The results of amino acid analyses suggested that this cytochrome P448 is similar to cytochrome P448 of 3-methylcholanthrene-treated rats.

Metabolism of Prolintane in Rats and the Effect of Prolintane Metabolites on General Activities in Mice

Abstract1. The metabolism of prolintane in vivo has been investigated in rats; the pharmacological effects in mice of the metabolites from rats and rabbits have been examined.2. In four rats receiving [3H]prolintane (50 mg/kg, intraperitoneal) about 57% of the radioactivity was excreted in the 48 h urine.3. A pyrrolidine ring-opened metabolite (15% dose) and p-hydroxyprolintane (5% dose) were excreted as predominant metabolites together with traces of unchanged drug and oxoprolintane.4. The general activities (ambulation and rearing) of mice were increased significantly by p-hydroxyprolintane and (ω — 1)-hydroxyprolintane as well as prolintane. Oxoprolintane was not effective on ambulation, but partially effective on rearing. However, PPGABA showed a depressant effect in mice rather than being stimulatory.

Effect of d-Limonene and related compounds on bile flow and biliary lipid composition in rats and dogs

Abstract d-Limonene enhanced bile flow in rats and dogs with a dose response correlation. The choleretic activity was much higher in the metabolites of d-limonene such as p-mentha-1,8-dien-10-ol, p-menth-1-ene-8,9-diol and p-mentha-1,8-dien-6-ol than d-limonene, and this suggested that the choleretic activity of d-limonene was attributable at least in part to its metabolites. The choleretic activities of esters of p-menth-1-ene-8,9-diol with acetic acid, propionic acid, stearic acid, palmitic acid, linoleic acid, benzoic acid, salicylic acid, α-naphthylacetic acid and nicotinic acid were also investigated in rats. Among these compounds, acetate, propionate and nicotinate possessed considerable, but lesser activities than the original diol. In dogs, however, the choleretic activity of p-menth-l-ene-8,9-diol acetate and propionate was much higher than that of original diol, suggesting that the choleretic activity of these esters is attributable to the esters themselves. d-Limonene decreased the ratio of biliary bile salts and phospholipids to cholesterol, whereas p-menth-l-ene-8,9-diol increased it.