Induction of drug-metabolizing enzymes by xenobiotics

Bock, Karl Walter; Lipp, Hans‐Peter; Bock-Hennig, Barbara S.

doi:10.3109/00498259009046831

Cited by 75 publications

(24 citation statements)

References 39 publications

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“…UDP-glucuronosyltransferase, one of the extracted genes, is of major importance in conjugation and subsequent elimination of potentially toxic xenobiotics (Bock et al, 1990). PB and OPZ, which lowered plasma TG level in the present study, were previously reported to have the ability to induce this enzyme (Bock et al, 1990;Masubuchi et al, 1997). These results indicated that the xenobiotics metabolism pathway might have a role in plasma TG decrease.…”

Section: Discussionsupporting

confidence: 57%

“…GO analysis showed that the carboxylic acid metabolism-and glucuronosyltransferase activityrelated genes were also affected by TG-decreasing compounds (Table 3). UDP-glucuronosyltransferase, one of the extracted genes, is of major importance in conjugation and subsequent elimination of potentially toxic xenobiotics (Bock et al, 1990). PB and OPZ, which lowered plasma TG level in the present study, were previously reported to have the ability to induce this enzyme (Bock et al, 1990;Masubuchi et al, 1997).…”

Section: Discussionmentioning

confidence: 87%

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Gene Expression Profiling of Rat Liver Treated With Serum Triglyceride-Decreasing Compounds

et al. 2007

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-We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for interpretation of plasma triglyceride (TG) decrease, we extracted 218 probe sets of rat hepatic genes from data of 15 drugs that decreased the plasma TG level but differentially affected food consumption. Pathway and gene ontology analysis revealed that the genes belong to amino acid metabolism, lipid metabolism and xenobiotics metabolism. Principal component analysis (PCA) showed that 12 out of 15 compounds were separated in the direction of PC1, and these 12 were separated in the direction of PC2, according to their hepatic gene expression profiles. It was found that genes with either large or small eigenvector values in principal component PC 2 were those reported to be regulated by peroxisome proliferator-activated receptor (PPAR)α or constitutive androstane receptor (CAR), respectively. In fact, WY-14,643, clofibrate, gemfibrozil and benzbromarone, reported to be PPARα activators, distributed to the former, whereas propylthiouracil, omeprazole, phenobarbital, thioacetamide, methapyrilene, sulfasalazine and coumarin did to the latter. We conclude that these identified 218 probe sets could be a useful source of biomarkers for classification of plasma TG decrease, based on the mechanisms involving PPARα and CAR.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 87%

Gene Expression Profiling of Rat Liver Treated With Serum Triglyceride-Decreasing Compounds

et al. 2007

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“…Previous studies showed that the V max for cytochrome P450-dependent monooxygenation of MXC was increased in 3-MC-induced catfish, compared with untreated controls (Stuchal et al, 2006), so the finding that V max values for both phase II pathways were increased suggests that catfish co-exposed to MXC and polycyclic aromatic hydrocarbons may exhibit an overall increased biotransformation of MXC, and perhaps more rapid elimination. The finding that glucuronidation was increased by 3-MC treatment was not unexpected, as there are other reports of induction of glucuronidation by polycyclic aromatic hydrocarbons, both in fish, including catfish (Andersson et al, 1985;Clarke et al, 1992;Gaworecki et al, 2004) and in mammals (Bock et al, 1990). The 3-MC-induced increases in sulfotransferase activities of OH-MXC and HPTE, both very poor substrates for sulfonation, prompted a study of the effect of 3-MC on the sulfonation of a better substrate, 3-OH-BaP.…”

Section: Induction Of Sulfonation and Glucuronidationmentioning

confidence: 99%

Glucuronidation and sulfonation, in vitro, of the major endocrine-active metabolites of methoxychlor in the channel catfish, Ictalurus punctatus, and induction following treatment with 3-methylcholanthrene

2008

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The organochlorine pesticide, methoxychlor (MXC), is metabolized in animals to phenolic monoand bis-demethylated metabolites (OH-MXC and HPTE respectively) that interact with estrogen receptors and may be endocrine disruptors. The phase II detoxication of these compounds will influence the duration of action of the estrogenic metabolites, but has not been investigated extensively. In this study, the glucuronidation and sulfonation of OH-MXC and HPTE were investigated in subcellular fractions of liver and intestine from untreated, MXC-treated and 3-methylcholanthrene (3-MC)-treated channel catfish, Ictalurus punctatus. MXC-treated fish were given i.p. injections of 2 mg MXC/kg daily for 6 days and sacrificed 24 hr after the last dose. The 3-MC treatment was a single 10 mg/kg i.p. dose 5 days prior to sacrifice. In hepatic microsomes from control fish, the V max value (mean ± S.D., n=4) for glucuronidation of OH-MXC was 270 ± 50 pmol/ min/mg protein, higher than found for HPTE (110 ± 20 pmol/min/mg protein). For each substrate, the V max values observed in intestinal microsomes were approximately twice those found in the liver. The K m values for OH-MXC and HPTE glucuronidation in control liver were not significantly different and were 0.32 ± 0.04 mM for OH-MXC and 0.26 ± 0.06 mM for HPTE. The K m for the co-substrate, UDPGA, was higher in liver (0.28 ± 0.09 mM) than intestine (0.04 ± 0.02 mM). Treatment with 3-MC but not MXC increased the V max for glucuronidation in liver and intestine. Glucuronidation was a more efficient pathway than sulfonation for both substrates, in both tissues. The V max values for sulfonation of OH-MXC and HPTE respectively in liver cytosol were 7 ± 3 and 17 ± 4 pmol/min/mg protein and in intestinal cytosol were 13 ± 3 and 30 ± 5 pmol/min/mg protein. Treatment with 3-MC but not MXC increased rates of sulfonation of OH-MXC and HPTE and the model substrate, 3-hydroxy-benzo(a)pyrene in both intestine and liver. Comparison of the kinetics of the conjugation pathways with those published for the demethylation of MXC showed that formation of the endocrine-active metabolites was more efficient than either conjugation pathway. Residues of OH-MXC and HPTE were detected in extracts of liver microsomes from MXC-treated fish. This work showed that although OH-MXC and HPTE could be eliminated by glucuronidation and sulfonation, the phase II pathways were less efficient than the phase I pathway leading to formation of these endocrine-active metabolites.

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“…PHB is a particularly important agent for the enzyme induction approach to the study of xenobiotic defensive mechanisms, as it is known to induce a number of drug-metabolizing enzymes. While most attention has focused on the induction of CYPs by PHB (19,20), the compound is also known to induce other detoxification enzymes, including GSTs (21,22) and UDP glucuronosyltransferases (UDPGTs) (23).…”

mentioning

confidence: 99%

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

Kotze

Ruffell

Ingham

2014

Antimicrob Agents Chemother

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We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC 50 ) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field.

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Induction of drug-metabolizing enzymes by xenobiotics

Cited by 75 publications

References 39 publications

Gene Expression Profiling of Rat Liver Treated With Serum Triglyceride-Decreasing Compounds

Gene Expression Profiling of Rat Liver Treated With Serum Triglyceride-Decreasing Compounds

Glucuronidation and sulfonation, in vitro, of the major endocrine-active metabolites of methoxychlor in the channel catfish, Ictalurus punctatus, and induction following treatment with 3-methylcholanthrene

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

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