Many food products, particularly fruits and vegetables, contain natural products that affect biotransformation enzymes. These may be expected to affect the rate of biotransformation of PCBs that are metabolized by the affected enzymes. The first step in PCB metabolism is cytochrome P450-dependent monooxygenation. Natural products present in cruciferous vegetables have been shown to selectively up-regulate CYP1A1 and CYP1A2 isozymes on chronic ingestion, and may lead to increased metabolism of those PCB congeners that are substrates for the induced P450s. On the other hand, several natural products selectively inhibit monooxygenation, especially in the intestine, and may lead to increased bioavailability and reduced metabolism of dietary PCBs. Food natural products are known to affect phase II pathways important in the detoxication of hydroxylated PCBs, namely UDP-glucuronosyltransferase and PAPS-sulfotransferase. Continual dietary exposure to chrysin and quercetin, found in fruits and vegetables, induces UGT1A1 and may reduce exposure to hydroxylated PCBs through increased glucuronidation. These and other natural products are also inhibitors of glucuronidation and sulfonation, potentially leading to transient decreases in the elimination of hydroxylated PCBs. In summary, the expected effects of food natural products on PCB biotransformation are complex and may be biphasic, with initial inhibition followed by enhanced biotransformation through monooxygenation and conjugation pathways.
The antibacterial substance triclosan, 5‐chloro‐2‐(2,4‐dichlorophenoxy)‐phenol, is used in many consumer products resulting in widespread human exposure. Triclosan forms glucuronide and sulfate conjugates which are excreted in urine, however it is not known which UDP‐glucuronosyltransferase (UGT) isoform(s) catalyze triclosan glucuronidation. This study examined rates of glucuronidation of several concentrations of triclosan catalyzed by expressed human UGTs and individual human liver microsomes (HLMs) with 1 mM 14C‐UDP‐glucuronic acid as co‐substrate. The UGT isozymes studied are found in the human liver and intestine, the likely sites of triclosan glucuronidation. The results indicated UGT1A1 exhibited the highest glucuronidation efficiency (Vmax/Km). UGTs 1A3, 1A6,1A7, 1A8 and 1A9 also readily catalyzed triclosan glucuronidation, but UGTs 1A4, 1A10, 2B4, 2B7 and 2B15 were less active. Studies of triclosan glucuronidation in 23 individual HLMs were conducted at 0.01 mM and 1mM triclosan concentrations. More than 15‐fold variability in specific activity was found in the HLM samples at both concentrations of triclosan. These results suggest that clearance of triclosan by glucuronidation may be expected to vary considerably between individuals. Supported in part by R21 ES 020545 and an award from the University of Florida
Dichloroacetate (DCA) is an investigational drug that can stimulate mitochondrial energy metabolism by inhibiting pyruvate dehydrogenase kinase. We hypothesize that DCA could be used in high‐risk pregnancy to reduce perinatal mitochondrial deficiency and resulting cardiac dysfunction in at‐risk fetuses and are testing this postulate in a pregnant sheep model. DCA is metabolized by the enzyme glutathione transferase zeta1 (GSTZ1) to glyoxylate. GSTZ1 is not expressed in human fetal liver, but expression rises after birth. Furthermore, DCA inactivates GSTZ1, resulting in altered pharmacokinetics with repeated dosing. The objectives of this research were (1) to investigate the relative expression of GSTZ1 in maternal and fetal sheep liver from untreated controls close to full term (140 days gestation) and (2) to determine if treatment of sheep with DCA resulted in reduced expression of GSTZ1. We administered DCA intravenously to either the ewe or the fetus at daily divided doses of 25 mg/kg for three to five days prior to sacrifice 24 h after the last dose. We used samples of maternal and fetal liver to prepare cytosol and mitochondria and employed a custom‐made polyclonal antibody to rat GSTZ1 to measure expression relative to a single rat hepatic cytosol standard by Western blot. The sheep liver samples exhibited good cross‐reactivity to the rat antibody. Surprisingly, expression of GSTZ1 in the full‐term fetal liver cytosol fractions from controls was similar to that in the control maternal liver. Treatment with DCA resulted in reduced expression in both maternal and fetal liver cytosol fractions to less than 10% of the control values. In control fetuses, mitochondrial expression of GSTZ1 was 17.6 ± 7.6% of the cytosolic expression. In the DCA‐treated group, mitochondrial expression decreased and levels were undetectable in one‐half of the fetal sheep. These studies demonstrate that (1) GSTZ1 expression in liver cytosol and mitochondria in the late fetal period varies with animal species and (2) repeated treatment with DCA results in reduced GSTZ1 expression, which is likely to alter DCA pharmacokinetics.Support or Funding InformationSupported in part by the US Public Health Service, grant R21HD91599This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glutathione transferase zeta 1 (GSTZ1)/maleylacetoacetate isomerase (MAAI) is a critical enzyme in tyrosine catabolism via its trans‐isomerization of maleylacetoacetate (MAA) and maleylacetone (MA). GSTZ1 also catalyzes the metabolism of dichloroacetate (DCA), an investigational drug utilized in the treatment of cancer and mitochondrial diseases. The pharmacology and toxicity of DCA are influenced, in part, by subject age. DCA is a mechanism‐based inactivator of GSTZ1, and repetitive DCA dosing results in the auto‐inhibition of DCA metabolism. Consequently, the chronic use of DCA in adults can lead to development of reversible peripheral neuropathy. However this effect is seldom observed in children, who metabolize DCA more quickly than adults. The tissue accumulation of DCA, MAA, and MA, due to GSTZ1 degradation, may be a mechanism responsible for DCA toxicity. Although liver is the main site of GSTZ1 expression and activity, extrahepatic tissues also express GSTZ1. Following a single dose of DCA to female rats, GSTZ1 expression and activity were reduced in liver to a greater extent than in kidney, brain and heart. However, the role of extrahepatic tissues in metabolism of DCA, MAA, and MA following repeated doses of DCA that mimic therapy has not been studied. Therefore, we examined the relative tissue expression of GSTZ1 following multiple doses of DCA. Adult female Sprague Dawley rats, 8 per group, and juvenile female Sprague Dawley rats, 4 per group, were treated with sodium DCA (100 mg/kg) or sodium acetate (100 mg/kg) by oral gavage daily for 8 consecutive days. On the 9th day the tissues were removed and used to prepare cytosolic and mitochondrial subcellular fractions. GSTZ1 expression was then assessed via Western blot using a polyclonal antibody to rat GSTZ1. In comparison to the same tissue in acetate‐treated adults, the expression of cytosolic GSTZ1 remaining in the liver, kidney, heart and brain of DCA‐treated adults was 2.8%, 9.8%, 8.6% and 5.7%, respectively, with liver retaining the highest expression at 0.030 ± 0.009 ng GSTZ1/μg protein (mean ± S.E.). Similarly, the expression of cytosolic GSTZ1 in DCA‐treated juveniles was greatest in liver (0.044 ± 0.014), whereas extrahepatic tissues were 20‐fold lower. Expression of mitochondrial GSTZ1 in DCA‐treated animals was highest in juvenile liver (0.016 ± 0.005) and adult kidney (0.048 ± 0.007). Considering the higher protein yield and larger size of the liver, compared with extrahepatic tissues, most DCA metabolism is expected to occur in the liver, even after repeated dosing. Given the greater proportion of liver to body weight in young rats, the hepatic metabolism of DCA is predicted to be augmented within this age group. This is consistent with the higher clearance of DCA in young populations, as children may retain a higher capacity for the GSTZ1‐catalyzed metabolism of DCA due to relative liver size.Support or Funding InformationSupported in part by the US Public Health Service GM 099871This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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