Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Abstract

Nonylphenol (NP) is a breakdown product of nonylphenol ethoxylates, which are used in a variety of industrial, agricultural, household cleaning, and beauty products. NP is one of the most commonly found toxicants in the United States and Europe and is considered a toxicant of concern because of its long half-life. NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s. No study to date has examined the gender-specific effects of NP on hepatic P450 expression. We provided NP at 0, 50 or 75 mg/kg/day for 7 days to male and female FVB/NJ mice and compared their P450 expression profiles. Q-PCR was performed on hepatic cDNA using primers to several CYP isoforms regulated by PXR or its relative, the constitutive androstane receptor (CAR). In female mice, NP induced Cyp2b10 and Cyp2b13, and downregulated the female-specific P450s, Cyp3a41 and Cyp3a44. In contrast, male mice treated with NP showed increased expression of Cyp2a4, Cyp2b9, and Cyp2b10. Western blots confirmed induction of Cyp2b subfamily members in both males and females. Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males. The overall increase in female-predominant P450s in males (Cyp2a4, 2b9) and the decrease in female-predominant P450s in females (Cyp3a41, 3a44) suggest that NP is in part feminizing the P450 profile in males and masculinizing the P450 profile in females. Testosterone hydroxylation was also altered in a genderspecific manner, as testosterone 16α-hydroxylase activity was only induced in NP-treated males. In contrast, NP-treated females demonstrated a greater propensity for metabolizing zoxazolamine probably due to greater Cyp2b induction in females. In conclusion, NP causes gender-specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females.

CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

“…As shown in Figure 7, PF9601N significantly inhibited the formation of 6β-hydroxytestosterone, marker of CYP3A activity, by about 78% as compared to control values. Furthermore the 30% inhibition of 15β-hydroxytestosterone formation, catalysed by CYP3A confirmed the previous data (28). The inhibition study performed on human liver microsomes showed that, as observed in mouse liver microsomal preparations, only ketoconazole significantly inhibited by about 30% PF9601N Ndealkylation rate (Figure 8).…”

Lack of gender effect on the pharmacokinetics of oxytetracycline in Fenneropenaeus chinensis after intramuscular administration

“…This is not in accordance with the documented in other animals (Zou et al, 2007;Hernandez et al, 2006). The underlying mechanism of genderspecific pharmacokinetics has been related to molecular and physiological factors (Meibohm et al, 2002).…”

“…The amount of CYP450 in female rats is 10%-30% lower than that in male rats (Zou et al, 2007). Hernandez (2006) examined the gender-specific effects of nonylphenol on hepatic CYP450 expression and found that in female mice nonylphenol induced CYP2d10 and CYP 2d13 and down-regulated female-specific p450s, CYP 3a41, and CYP 3a44, whereas male mice treated with nonylphenol showed increased expression of CYP 2a4, CYP 2b9, and CYP 2b10. It is inferred that the different result in our study may due to the lack of genderspecific effects of OTC on hepatic CYP450 expression.…”

Gastrectomy Increases the Expression of Hepatic Cytochrome P450 3A by Increasing Lithocholic Acid-Producing Enteric Bacteria in Mice

“…27) Therefore, we examined whether nuclear CAR levels increased by the gastrectomy. Hepatic nuclear fractions were prepared, and CAR protein expression levels were examined by Western blot to determine the level of nuclear The mice of the sham operation group (white) and the gastrectomy group (black) were allowed free access to the diet.…”

“…Therefore, when the expression of CYP3A11 is regulated by CAR, the expression of not only CYP3A11 but also CYP2B10 is expected to increase. The expression of CYP2B10 was also examined 27) (Fig. 5).…”