Gender-related difference in the toxicity of 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole in rats: Relationship to the plasma concentration,in vitrohepatic metabolism, and effects on hepatic metabolizing enzyme activity

Abstract

Previously, we showed that the toxic susceptibility of male rats to an ultraviolet absorber, 2-(2'-hydroxy- 3',5'-di-tert-butylphenyl)benzotriazole (HDBB), was nearly 25 times higher than that of females. The present study aimed to clarify the mechanism of gender-related differences in HDBB toxicity. Male and female rats were given HDBB by gavage at 0.5, 2.5, or 12.5 mg/kg/day for 28 days, and plasma HDBB levels were measured at various time points by using liquid chromatography-tandem mass spectrometry. HDBB was rapidly absorbed and eliminated from the plasma in both sexes, and no sexual variations were found in the plasma levels. In the plasma, HDBB metabolites were not detected at any dose by the liquid chromatography-photodiode array detector. In an in vitro metabolic study using hepatic microsomes from male and female rats, HDBB was slightly metabolized, but no sexual differences were found in the residual HDBB ratio after a 60-minute incubation with an NADPH-generation system. Following 28-day HDBB administration, sexually different changes were found in cytochrome P450-dependent microsomal mixed-function oxidase activities in the liver. In males, 7-ethoxyresorufin O-deethylase activity decreased and lauric acid 12-hydroxylase activity increased at all doses. Decreases in aminopyrine N-demethylase activity and testosterone 2alpha- and 16alpha-hydroxylase activity were also found at 2.5 mg/kg and above in males. In females, the only significant change was increased lauric acid 12-hydroxylase activity at 12.5 mg/kg. These findings indicate that HDBB would have hepatic peroxisome proliferative activity, and the difference in susceptibility of male and female rats to this effect might lead to marked gender-related differences in HDBB toxicity.

Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2’-hydroxy-3’,5’-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences

“…As for HDBB, we previously found that there was no sex-related difference in blood HDBB levels, and in the blood, no metabolites were detected. This finding suggests that the sex-related difference in HDBB toxicity is attributable exclusively to sex-related difference in toxicodynamic factors (Hirata-Koizumi et al, 2009a).…”

“…The sex-related difference in HDBB toxicity was reduced by castration (Hirata-Koizumi et al, 2008a) and was not observed in preweaning rats (HirataKoizumi et al, 2008b). In contrast, there was no sex-related difference in plasma HDBB levels in young rats administered HDBB (Hirata-Koizumi et al, 2009a). These findings suggest that toxicodynamic factors account for sex-related differences in HDBB toxicity (HirataKoizumi et al, 2009b).…”

Disappearance of gender‐related difference in the toxicity of benzotriazole ultraviolet absorber in juvenile rats

“…These results indicate no gender‐related differences in the susceptibility to toxic effects of HDBB in preweaning rats. The rate of changes in the relative liver weight clearly showed a lack of gender‐related differences in HDBB hepatotoxicity in preweaning rats (Figure 4 (Hirata‐Koizumi et al. 2009).…”

“… Plasma 2‐(2′‐hydroxy‐3′,5′‐di‐ tert ‐butylphenyl)benzotriazole (HDBB) concentrations against time after HDBB administration to male and female rats. HDBB was given by gavage to male and female rats for 28 days, starting at 5 weeks of age, and blood samples were collected from the jugular vein before and 1, 2, 5, 8, and 24 hours after the 28th dose (Hirata‐Koizumi et al. 2009).…”

“…In the present review, we summarize the toxicity of HDBB and its marked gender‐related difference in young rats, and then describe the toxicity in castrated and preweaning rats. Finally, we discuss the possible mechanism for the gender‐related difference in young rats, based on our most recent work (Hirata‐Koizumi et al. 2009).…”