Comparative study of the hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by microsomes of various rat and human tissues

Abstract

Hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by various tissue microsomes and plasma of rats, as well as human liver and small-intestinal microsomes, was investigated and the structure-metabolic activity relationship was examined. Rat liver microsomes showed the highest activity toward parabens, followed by small-intestinal and lung microsomes. Butylparaben was most effectively hydrolyzed by the liver microsomes, which showed relatively low hydrolytic activity towards parabens with shorter and longer alkyl side chains. In contrast, small-intestinal microsomes exhibited relatively higher activity toward longer-side-chain parabens, and showed the highest activity towards heptylparaben. Rat lung and skin microsomes showed liver-type substrate specificity. Kidney and pancreas microsomes and plasma of rats showed small-intestinal-type substrate specificity. Liver and small-intestinal microsomal hydrolase activity was completely inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. Ces1e and Ces1d isoforms were identified as carboxylesterase isozymes catalyzing paraben hydrolysis by anion exchange column chromatography of Triton X-100 extract from liver microsomes. Ces1e and Ces1d expressed in COS cells exhibited significant hydrolase activities with the same substrate specificity pattern as that of liver microsomes. Small-intestinal carboxylesterase isozymes Ces2a and Ces2c expressed in COS cells showed the same substrate specificity as small-intestinal microsomes, being more active toward longer-alkyl-side-chain parabens. Human liver microsomes showed the highest hydrolytic activity toward methylparaben, while human small-intestinal microsomes showed a broadly similar substrate specificity to rat small-intestinal microsomes. Human CES1 and CES2 isozymes showed the same substrate specificity patterns as human liver and small-intestinal microsomes, respectively.

Methylparaben and butylparaben alter multipotent mesenchymal stem cell fates towards adipocyte lineage

“…It is believed that parabens are subject to hydrolysis by non-specific esterase in the body, mostly in the gastrointestinal tract and the liver. In addition, the efficiency and pattern of hydrolysis depend on the length of alkyl side chain and the location of the hydrolysis [55, 56]. Butylparaben was found to be more efficiently hydrolyzed than methylparaben by microsomes prepared from rat liver and small intestine as well as by rat plasma [56].…”

“…In addition, the efficiency and pattern of hydrolysis depend on the length of alkyl side chain and the location of the hydrolysis [55, 56]. Butylparaben was found to be more efficiently hydrolyzed than methylparaben by microsomes prepared from rat liver and small intestine as well as by rat plasma [56]. Therefore, it is conceivable that higher hydrolysis of butylparaben in the exposed mice may have contributed to less pronounced effects of butylparaben on total white fat mass in vivo .…”

Characterization of Species Differences in Tissue Diltiazem Deacetylation Identifies Ces2a as a Rat-Specific Diltiazem Deacetylase

“…Among those chemicals, by acyl group size, the descending order is palmitoyl-CoA, isocarboxazid, butanilicaine, malathion, and acetanilide. In addition, Ozaki et al (2013) investigated the substrate specificity of rat Ces isoforms using parabens with various alkyl chain lengths, although the substrate specificities of Ces1d, Ces1e, and Ces1f could not be clearly determined from the size of the alcohol or acyl moieties. In the same report, although information regarding the substrate specificity of rat Ces2 was very limited, it was revealed that rat Ces2a appears to prefer compounds with a large alcohol moiety, which is a characteristic of diltiazem.…”

“…Indeed, CES1 prefers compounds with a large acyl group and a small alcohol group, whereas CES2 prefers compounds with a small acyl group and a large alcohol group. Recently, Ozaki et al (2013) measured the hydrolase activity of several rat Ces enzymes toward paraben derivatives and found that the substrate specificity of the Ces1 and Ces2 families does not necessarily correspond with that in humans. In addition, it has been shown that most substrates were hydrolyzed by multiple isoforms in rats (Robbi and Beaufay, 1994;Sanghani et al, 2002).…”

Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products

“…Indeed, unchanged parabens are used as urinary biomarkers of exposure in humans (Ye et al, 2006). However, several carboxylesterase isozymes catalyzing hydrolysis of parabens have been identified in rat and human hepatic and small-intestinal microsomes (Ozaki et al, 2013). The main metabolic pathway in mammals is hydrolysis to 4-hydroxybenzoic acid and alcohols, which are excreted after conjugation with glucuronide, sulfate or glycine (Tsukamoto and Terada, 1964).…”