P-Naphthoflavone

The dissociation between cardiotoxicity and carcinogenesis can be visuahzed in zebrafish embryos exposed to known dioxin like carcinogens, like benzo[a]p3rene, or to noncarcinogenic AhR ligands, as p-naphthoflavone (Fig. 5) [41, 43]. The conclusion that cardiotoxic effects in zebrafish (and presumably, other vertebrates ) embryos occur by exposition to AhR hgands so-far considered... 

P-naphthoflavone or Aroclor 1254 did not significantly alter coumarin hepatotoxicity in C3H/He mice, while hepatic microsome metabolism of [ C]coumarin doubled following administration of either inducer. In DBA/2 mice, pretreatment with either P-naphthoflavone or Aroclor 1254 did not affect coumarin-induced hepatotoxicity. 

UGT1A6 is inducible by polycyclic aromatic hydrocarbons (PAH). UGT1A6 was also induced in human hepatocytes by p-naphthoflavone and in some, but not all, hepatocyte preparations by rifampin. APAP glucuronidation appears to be increased in smokers, perhaps due to PAH-mediated induction of UGT1A6. Serotonin glucuronidation was doubled in microsomes from persons with moderate-to-heavy alcohol use (54). 

Standard rat liver S-9 prepared by inducing male Sprague-Dawley rats with Aroclor-1254 or Phenobarbital and/or p-naphthoflavone... 

Shahi GS, Das PN, Moochhala SM. 1-Methyl-4-phenyl-1,2,36-tetrahydropyridine-induced neurotoxicity partial protection against striato-nigral dopamine depletion in C57BL/6J mice by cigarette smoke exposure and by p-naphthoflavone-pretreatment. Neurosoi Lett 1991 127 247-250. 

Jenner MA, Plummer JL, Cousins MJ. Influence of isoniazid, phenobarbital, phet toin, pr -nenolone 16-a carbonitrile, and p-naphthoflavone on haloftimie metabolism and hepatotoxicity, Drug Metab Dispos (1990) 18, 819-22. 

Figure 1. Chromatogram showing the separation of the cis and trans isomers of 3-hexen-l-ol (cis/trans 3-H) and a and p-naphthoflavone (NF) on a 25-cm p-CD column using 50% aqueous methanol as the mobile phase. [Conditions flow rate = 1.0 ml/min., 24 C, and chromatographic system II. The wavelength for detection of the 3-hexen-l-ols was 220 nm while that for the naphthof lavone s was 273 nm.]...

Intestinal cytochrome P-450, in common with its hepatic isozymes, is induced by a wide variety of xenobiotics. Not only intraluminal iron but also selenium is critically required for basal maintenance of intestinal cytochrome P-450 content and its dependent mixed-function oxidase. Accordingly, acute deprivation of either element for as short a period as a single day reduced basal intestinal cytochrome P-450 content by limiting the formation and/or availability of its prosthetic heme (Pascoe et al. 1983). Whereas both intraluminal iron and selenium were required for maintenance of the prosthetic apocytochrome moiety of the constitutive intestinal isozyme, only intraluminal selenium was required for the viability of apocytochrome of the P-naphthoflavone-inducible P-448 (Pascoe and Correia 1985). 

Figure 6. All-tram retinoic acid (29), 9-cis retinoic acid (30), Ro 41-5253 (31), pentobarbital (32) and P-naphthoflavone (33).

Trp-P-1 acetate form and phenobarbital sodium salt were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Com oil, and P-naphthoflavone were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Antirat CYPlAl antiserum was purchased from Daiichi Pure Chemicals Co., Ltd. (Tokyo, Japan). An antibody to caspase-3 was purchased from Santa Cruz Biotechnology, Inc. (Santa Curz, CA). Secondary antibody to goat IgG was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other chemicals were of the highest quality commercially available. 

Figure 1. Expression of CYP lAl in P NF-treated rat hepatocytes. Hepatocytes were isolated from P-naphthoflavone (f-NF) and com oil (ControlJ-treated rats. After culture for 2 or 20 h, microsomal proteins were prepared from hepatocytes and loaded onto a 10% SDS-polyacrylamide gel (10 pg protein, each). (A) CYP lA level by Western blotting (B) EROD activity were measured as described in Materials and methods. Values are presented as means S.D.

Figure 4. Suppression of DNA fragmentation caused by Trp-P-1 in P-NF-treated rat hepatocytes. Hepatocytes were isolated from P-naphthoflavone (P-NF) and corn oil (C)-treated rats and cultured for 20 h. These hepatocytes were treated with Trp-P-1 for 6 h, and DNA fragmentation was analyzed by 2% agarose gel electrophoresis.

Miranda, C. L., Chung, W. G., Wang-Buhler, J.-L., Musafia-Jeknic T., Baird, W. M. Buhler D. R. (2006). Comparative in vitro metabolism of benzo[a]pyrene by recombinant zebrafish CYPIA and liver microsomes from P-naphthoflavone-treated rainbow trout. Aquatic Toxicology, 80, 101-108. 

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