Polychlorinated biphenyl (PCB) induction of CYP3A4 enzyme activity in healthy Faroese adults

https://doi.org/10.1016/j.taap.2007.07.002Get rights and content

Abstract

The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p′-chlorophenyl)ethane (o,p′-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18–60 years, the CYP3A4 activity was determined based on the urinary 6β-hydroxycortisol/cortisol (6β-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6β-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6β-OHC/FC ratio than men (p = 0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6β-OHC/FC ratios and ∑PCB, PCB–TEQ and p,p′-DDE, o,p′-DDT and HCB, respectively, but the associations were statistically significant for men only.

Introduction

The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances (Guengerich and Shimada, 1991, Nebert and Dalton, 2006). A commercial polychlorinated biphenyl (PCB) mixture (Okey, 1990, Lake et al., 1996), 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p′-chlorophenyl)ethane (o,p′-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p-DDE) (Medina-Diaz et al., 2007) have been found to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor, thereby resulting in increased production of CYP3A4 mRNA and higher activity levels (Gibson et al., 2002, Harmsen et al., 2007, Medina-Diaz et al., 2007). However, this induction of CYP3A4 has not yet been investigated in humans.

The residents of the Faroe Islands are exposed to elevated levels of PCBs and other environmental persistent organohalogen pollutants (POPs), e.g. DDT and DDE. The main source is traditional food, especially blubber from the pilot whale, which accumulates these pollutants (Bloch et al., 1990, Grandjean et al., 2001, Deutch and Hansen, 2003, Longnecker et al., 2003). Thus, with their wide range of exposures, the Faroese appear to be a highly appropriate population for studying a possible inductive effect of POPs on the CYP3A4 activity in humans. A high activity of another P450 enzyme, CYP1A2, was previously observed in the Faroese population (Petersen et al., 2006) but the distribution characteristics of the CYP3A4 phenotype in Faroese have not yet been described.

In humans, CYP3A4 metabolizes over one-half of clinically used drugs (Zhou et al., 2004, Thummel and Wilkinson, 1998) and catalyzes the metabolism of a variety of exogenous and endogenous compounds (Shimada et al., 1989, Guengerich and Shimada, 1991, Shimida et al., 1994), including steroid hormones, such as testosterone, progesterone, and cortisol (Waxman et al., 1988, Harris et al., 1995). Significant interindividual variability in the expression and activity of CYP3A4 has been observed (Shimida et al., 1994, Wilkinson, 1996, Damkier and Brosen, 2000, Inagaki et al., 2002, Zhu et al., 2003), most likely a result of interplays of environmental, physiological and genetic factors (Gibson et al., 2002). CYP3A4 is involved in the 6β-hydroxylation of cortisol, and both cortisol and its metabolites are excreted in the urine. Though not an ideal probe (Streetman et al., 2000), the ratio of urinary 6β-hydroxycortisol (6β-OHC) to cortisol (FC) has long been used as a non-invasive indicator of the hepatic CYP3A4 activity (Park, 1981, Bienvenu et al., 1991, Watkins, 1994). We therefore applied this approach in this study to access the CYP3A4 activity in regard to the concentration of major PCBs and POPs.

Section snippets

Subjects

A total of 312 randomly selected healthy Faroese volunteers aged 18–60 years were recruited for the study. Detailed information on the recruitment has been previously described (Petersen et al., 2006). Despite the exclusion criteria of daily medication, four participants were currently taking medication (other than oral contraceptives (OCs)) at the time of the examination, yet these four subjects were included, since the medications were known not to affect the CYP3A4 activity.

Out of the 312

Results

The 6β-OHC/FC ratio showed a unimodal distribution with values ranging from 0.58 to 27.38 (Fig. 1). Women tended to have a higher 6β-OHC/FC ratio than men (t-test, p = 0.071) (Table 1, Table 2). Among potential confounders, age (as dichotomous variable), smoking, and use of OCs were not significant predictors of the 6β-OHC/FC ratio in the gender-stratified multiple regression analysis (Table 2) and therefore only sex was included in the final model (Table 3).

Table 4 shows the results of the

Discussion

This study is the first to determine the distribution characteristics of the CYP3A4 phenotype in the Faroese. As anticipated, the 6β-OHC/FC ratio showed a unimodal distribution. In addition, slightly elevated urinary 6β-OHC/FC ratios were found in women compared with men (Table 2). This finding is in accordance with some studies (Hunt et al., 1992, Inagaki et al., 2002, Galteau and Shamsa, 2003, Zhu et al., 2003), while other reports suggest the reverse situation with higher activity in men or

Acknowledgments

This study was supported by “Apotekerfonden af 1991”. The assistance of the staff at the Department of Occupational and Public Health in Tórshavn, Faroe Islands is highly appreciated.

References (39)

  • T. Bienvenu et al.

    A simple non-invasive procedure for the investigation of cytochrome P-450 IIIA dependent enzymes in humans

    Int. J. Clin. Pharmacol. Ther. Toxicol.

    (1991)
  • D. Bloch et al.

    Pilot whaling in the Faroe Islands, July 1986–July 1988

    North Atl. Stud.

    (1990)
  • P. Damkier et al.

    Quinidine as a probe for CYP3A4 activity: intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6

    Clin. Pharmacol. Ther.

    (2000)
  • M.M. Galteau et al.

    Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

    Eur. J. Clin. Pharmacol.

    (2003)
  • G.G. Gibson et al.

    Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man

    Xenobiotica

    (2002)
  • F.P. Guengerich et al.

    Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes

    Chem. Res. Toxicol.

    (1991)
  • J. Halling et al.

    Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

    Eur. J. Clin. Pharmacol.

    (2005)
  • R.Z. Harris et al.

    Gender effects in pharmacokinetics and pharmacodynamics

    Drugs

    (1995)
  • Cited by (0)

    View full text