Metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes

Abstract

Tributyltin and triphenyltin are metabolized by cytochrome P-450 system enzymes, and their metabolic fate may contribute to the toxicity of the chemicals. In the current study, the in vitro metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes was investigated to elucidate the metabolic competence for these compounds in humans. The metabolic reaction using microsome-NADPH system that is usually conducted was not applicable to in vitro metabolism of organotins, especially triphenyltin. We therefore examined the effects of dithiothreitol (DTT), one of the antioxidants for sulfhydryl groups, to determine the in vitro metabolism of tributyltin and triphenyltin. As a result, the treatment with 0.1 mM DTT in vitro increased the activity of the microsomal monooxygenase system for metabolism of tributyltin as well as triphenyltin; the total yield of tributyltin and triphenyltin metabolites as tin increased, respectively, by approximately 1.8 and 8.9 times for rat, 2.1 and 1.2 times for hamster, and 1.6 and 1.5 times for human. It is suggested that the organotins directly inactivate cytochrome P-450 because of the interaction with critical sulfhydryl groups of the hemoprotein. We confirmed the utility of this in vitro metabolic system using DTT in the hepatic microsomes of phenobarbital (PB)-pretreated and untreated hamsters. Thus, the in vitro metabolic system described here was applied to a comparative study of the metabolism of organotins in rats, hamsters and humans. Tributyltin was metabolized more readily than triphenyltin in all the species. In humans, the in vitro metabolic pattern resembled that of hamsters, which were susceptible to in vivo triphenyltin toxicity because of incompetent metabolism. It is possible that the hamster is a qualitatively and quantitatively suitable animal model for exploring the influence of tributyltin and triphenyltin in humans.

Toxic effect of triphenyltin onLemna polyrhiza

“…5 Organotins (TPT and TBT) directly inactivate cytochrome P-450 because of interaction with critical sulfhydryl groups of the hemoprotein, and TBT is metabolized more readily than TPT in rat, hamster and human. 6 The IC 50 s of TPT to hepatic glutathione Stransferase activity in marine fish Siganus canaliculatus and Sparus sarba are 10 and 28 µM, respectively. 7 Three types of hybrid catfish (Clarias gariepinus, Clarias macrocephalus) cell culture were established to screen toxicity of TPT.…”

In vitro metabolism of tributyltin and triphenyltin by human cytochrome P-450 isoforms

“…Triorganotin compounds appear to be more toxic than di-or monocompounds of the same chain length (Matsui et al, 1983;Blunden and Evans, 1990;Ema et al, 1996;Rozyckaroszak et al, 2000). Tributyltin and triphenyltin compounds rapidly undergo dealkylation or dearylation by CYP-dependent microsomal monooxygenase systems (Freitag and Bock, 1974;Kimmel et al, 1977;Blunden and Evans, 1990;Ohhira et al, 2003), which have a principal role in the metabolism of lipophilic xenobiotics, including drugs, carcinogens, and environmental pollutants (Guengerich, 1993;Lewis, 1996). The metabolic fate of tributyltin and triphenyltin compounds may thus contribute substantially to their toxicity (Ohhira et al, 1999(Ohhira et al, , 2000Cima et al, 2003;Appel, 2004).…”

“…We used an in vitro metabolic system to identify the human CYP principally responsible for the metabolism of tributyltin and triphenyltin. This system was used because it may closely reflect the in vivo metabolism of triorganotins as described previously (Ohhira et al, 2003).…”

“…(The final acetone concentration in the incubation mixture was less than 0.05%.) This concentration of organotin was adapted from the optimal concentration used in an earlier study (Ohhira et al, 2003) examining the metabolism of tributyltin and triphenyltin by rat, hamster, and human hepatic microsomes. The reaction mixture was incubated for 180 min at 37 • C, except for dealkylation of tributyltin with cDNA-expressed CYP enzymes (reaction time, 15 min at 37 • C) (Ohhira et al, 2006).…”

“…After studying the in vitro metabolism of tributyltin and triphenyltin, the parent triorganotins and their metabolites (diand mono-organotins and inorganic tin) in the reaction mixtures were assayed by gas chromatography (GC) as described previously (Ohhira et al, 2003).…”