The response of hepatic mono-oxygenase activities to Aroclor 1254 or 3-methylcholanthrene was investigated in wild-type and Cyp1a2(−/−) mice. Cytochrome P450 concentrations were similar in naïve Cyp1a2(−/−) and wild-type mice. There was no difference between naïve wild-type and Cyp1a2(−/−) animals in 7-ethoxyresorufin and 7-ethoxy-4-trifluoromethylcoumarin dealkylase activities, nor was the induction response after 3-methylcholanthrene any different between the two genotypes. However, both activities were induced to a higher extent in Cyp1a2(−/−) mice after Aroclor 1254. In contrast, 7-pentoxyresorufin dealkylation activity was lower in Cyp1a2(−/−) mice and this differential was maintained during induction by both agents. 7-Methoxy- and 7-benzoxyresorufin dealkylation activities were also lower than wild-type in naïve Cyp1a2(−/−) animals and during 3-methylcholanthrene induction, but showed accelerated induction in Cyp1a2(−/−) mice with Aroclor 1254. Bufuralol 1′- and testosterone 6β-hydroxylation activities, and P450 characteristics were evaluated 48 hours after inducer administration. Bufuralol 1′-hydroxylation, a sexual dimorphic activity (female > male) showed no genotype differences in naïve animals. Activity changes varied across gender and genotype, with 3-methylcholanthrene and Aroclor 1254 inducing in male Cyp1a2(−/−), and Aroclor 1254 inducing in female wild-type. Testosterone 6β-hydroxylation activity was 16% higher in Cyp1a2(−/−) mice and neither 3-methylcholanthrene nor Aroclor 1254 elicited induction. After Aroclor 1254, a 24% increase in P450 concentration with a hypsochromic shift in the ferrous-CO maximum characteristic of CYP1A enzymes occurred in wild-type, compared to no change in either parameter in Cyp1a2(−/−) mice. Induction changes with 3-methylcholanthrene were greater in wild-type mice, a 60% increase in concentration and ~2 nm hypsochromic shift versus a 10% increase and ~1 nm hypsochromic shift in Cyp1a2(−/−) mice. The study demonstrates that deletion of a single P450 can profoundly affect the induction response, as monitored with activities of other P450s, in a manner unrelated to the contribution of the deleted P450 to the activity.
Selenium‐containing compounds have demonstrated chemopreventive activity in a variety of chemically‐induced tumor models, but a unifying mechanism for this effect remains elusive. Altered disposition of chemicals and toxic metabolites may be contributing factors. Following dietary ingestion of selenocysteine pro‐drugs and selenocystine (15 ppm Se) for 1 month, mouse hepatic glutathione transferase, quinone oxidoreductase and microsomal epoxide hydrolase activities were elevated by 2‐butyl‐ and 2‐oxoselenazolidine‐4‐carboxylic acids (SCAs) and selenocystine, but not by 2‐cyclohexyl‐, 2‐phenyl‐, and 2‐(2′‐hydroxyphenyl)‐ SCAs. Expression of multidrug resistance‐associated proteins and other Abc transporters were evaluated by qPCR. Of 10 transporters examined, none responded in a pattern similar to the activities of the enzymes capable of being regulated via the Nrf2/ARE mechanism. Abcc3 (Mrp3) was increased only by 2‐butylSCA and no transporters were induced by 2‐oxoSCA or selenocystine. 2‐(2′‐Hydroxyphenyl)SCA was the only compound that induced expression of Abcc2 (Mrp2) and Abcb6. All the selenocompounds reduced the expression of Abcb11. Expression of Abcc1, Abcc4, Abcc5, Abcc6, and Abcg2 and Abca3, was not altered by any compound. Selenocompound regulation of Abc transporter expression appears to be compound dependent and unrelated to the Nrf2/ARE pathway.Support: GM 058913
Iron overload can lead to hepatic fibrogenesis and high liver iron is frequently associated with porphyria cutanea tarda (PCT), a disease characterized by hepatic accumulation of highly carboxylated porphyrins. To assess whether porphyrin accumulation could arise from impaired anion transport, ABC transporter expression in a porphyria‐susceptible mouse model was investigated by qPCR. Mice with the Urod+/– (uroporphyrinogen decarboxylase), Hfe−/− (hemochromatosis) genotype spontaneously develop PCT, with severely decreased UROD activity and hepatic iron overload. Control animals with only the Urod+/– genotype do not accumulate porphyrins and had no change in expression of twelve ABC transporters examined. Accompanying the high iron accumulation in the Hfe−/− animals, expression of Abca3, Abcb1a, and Abcc4 were increased and expression of Abcc2, Abcc6 and Abcg2 were decreased. In mice with the Urod+/–, Hfe−/− genotype, porphyrin accumulation was accompanied by elevated expression of Abca3 and Abcc4 while Abcc2 and Abcc6 expression was depressed. The elevation in expression of Abcb1a and depression of Abcc2 were no longer present. Novel in these animals was an elevation of Abcc1 expression. The porphyrin accumulation exacerbated the repression of Abcc2 and Abcc6 expression and attenuated the increase in Abca3 seen in Hfe−/− control mice.Supported USPHS Grants DK20503 and DK07115
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.