Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in rat and cultured rat hepatocytes

Abstract

1. The dose-response relationships for hepatic CYP2B induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were examined in the male F344/NCr rat. TCPOBOP, administered for 14 days at 0-1000 ppm in the diet, caused concentration-dependent induction of hepatic CYP2B1 protein and RNA, and of CYP2B-mediated catalytic activities (benzyloxy- and pentoxyresorufin O-dealkylation, and testosterone 16 beta-hydroxylation). ED50 values for CYP2B induction were > or = 300 ppm dietary TCPOBOP. The maximal inductions observed were 66-88% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 2. The EC50 values for hepatic CYP2B induction were 1.5-3.0 microM (based on serum TCPOBOP) and 15-20 mumol/kg liver. 3. The maximal inductions of isozymes of the CYP3A subfamily, of microsomal epoxide hydrolase, and of glutathione S-transferases Ya/Yc and Yb1/Yb2 in rats exposed to TCPOBOP were 58-74% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 4. The ED50 value for induction of benzyloxyresorufin O-dealkylation in cultured rat hepatocytes by TCPOBOP was determined to be 0.93 microM. The maximal induction of this activity caused by TCPOBOP was 87% of the maximum increases caused by phenobarbital. 5. The results indicate that TCPOBOP is a highly effective phenobarbital-type inducer in the rat when administered in the diet for 2 weeks at 1000 ppm. When extent of induction is related to serum total xenobiotic level, TCPOBOP would appear to be at least as potent as, if not more potent than, phenobarbital in the rat.

Role of CAR and PXR in xenobiotic sensing and metabolism

“…Subsequent studies using a humanized PXR mouse model and human cell lines further indicated that hPXR also regulates UGT1A1 expression [25, 36]. GST, another phase II conjugation enzyme, can be induced modestly by rifampicin [37], as well as by phenobarbital [38] and TCPOBOP [39], suggesting that PXR and CAR might regulate the expression of GSTs. Murine GST genes such as Gsta1, Gstm1, and Gstm2 have been shown to be regulated by both mPXR and mCAR [16, 40].…”

Hepatic cytochrome P450 2B induction by ethyl/ phenyl‐substituted congeners of phenobarbital in the B6C3F1 mouse

“…The striking potency of TCPOBOP in the mouse, together with the demonstration that certain structural features are required for activity within this class of agents (20,21), led to the hypothesis that a separate, high-affinity response element (receptor) for the bis(pyridy1oxy)benzenes existed in the mouse but not in the rat (17,18). More recently, however, we have demonstrated that most of the manifestations (CYP2B, CYP3A, epoxide hydrolase) of the phenobarbital-type response ure highly induced in the rat by TCPOBOP when the xenobiotic is administered continuously in the diet (22). Thus, the maximal CYP2B induction responses detected in rats exposed to a diet containing 1000 ppm TCPOBOP are 60430% of those evoked by 500 ppm phenobarbital, and the induction potency based on serum TCPOBOP levels appears to be as great as or greater than that of phenobarbital (22).…”

“…More recently, however, we have demonstrated that most of the manifestations (CYP2B, CYP3A, epoxide hydrolase) of the phenobarbital-type response ure highly induced in the rat by TCPOBOP when the xenobiotic is administered continuously in the diet (22). Thus, the maximal CYP2B induction responses detected in rats exposed to a diet containing 1000 ppm TCPOBOP are 60430% of those evoked by 500 ppm phenobarbital, and the induction potency based on serum TCPOBOP levels appears to be as great as or greater than that of phenobarbital (22). These findings suggest that similar response mechanisms for phenobarbital-type inducers, including TCPOBOP, exist in the two rodent species.…”

The cytochrome P450 2AA gene cluster in zebrafish (Danio rerio): Expression of CYP2AA1 and CYP2AA2 and response to phenobarbital-type inducers

“…In mammals, PB and a number of structurally diverse xenobiotics, including the highly potent 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and ortho -substituted polychlorinated biphenyl (PCB) congeners, strongly induce the expression of members of the CYP2B subfamily (Kopec et al, 2010; Nims et al, 1993; Smith et al, 1993a, 1993b; Vezina et al, 2004; Waxman, 1999). There is a long history of efforts to identify and demonstrate a CYP2B-like induction by PB or related compounds in fish (Bainy et al, 1999; Buhler and Wang-Buhler, 1998; Celander et al, 1996; Elskus and Stegeman, 1989; Förlin, 1980; Goksøyr, 1985; Iwata et al, 2002; Kleinow et al, 1990; Klotz et al, 1986; Stegeman et al, 1990).…”