Environmental influences on human foetal and placental xenobiotic metabolism

Summary The human foetus is more capable of metabolizing xenobiotics than foetuses of common laboratory animal species. However, xenobiotic metabolism in animal foetuses is inducible by the exposure of the mother to various inducers during late pregnancy. Xenobiotic metabolism in neonates is more easily inducible than in foetal animals. With respect to the human foetus at mid-pregnancy, the hepatic enzyme systems do not seem to be readily inducible by exogenous inducers, whereas the placental monooxygenase system is almost totally dependent on maternal cigarette smoking. In the human newborn, indirect evidence points to the possibility of induction by potential inducers. The ontogenetic development of xenobiotic metabolism is probably regulated by endogenous hormones. It is possible that environmental factors may affect these normal regulatory and imprinting phenomena and thus lead to permanent disturbances in xenobiotic metabolism.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

Lipoic Acid as a Potential First Agent for Protection from Mycotoxins and Treatment of Mycotoxicosis

Mycotoxins—toxic substances produced by fungi or molds—are ubiquitous in the environment and are capable of damaging multiple biochemical mechanisms, resulting in a variety of human symptoms referred to collectively as "mycotoxicosis." In fact, mycotoxins mimic multiple xenobiotics, not only with respect to their ultimate damage, but also in their routes of detoxification. This suggests potential therapeutic options for the challenging treatment of mycotoxicosis. In this brief review, the author examines the use of lipoic acid as an example of an inexpensive and available nutrient that has been shown to protect against, or reverse, the adverse health effects of mycotoxins.     

The potential of steroids and xenobiotic receptor polymorphisms in forecasting cyclosporine pharmacokinetic variability in young kidney transplant recipients

Ferraresso M, Turolo S, Belinghieri M, Tirelli AS, Grillo P, Groppali E, Edefonti A, Ghio L. The potential of steroids and xenobiotic receptor polymorphisms in forecasting cyclosporine pharmacokinetic variability in young kidney transplant recipients. Abstract: The steroids and xenobiotics receptor (SXR) up‐regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.‐205_‐200delGAGAAG and 7635 A>G. CyA trough levels and CyA weight‐adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight‐adjusted daily dose were comparable on four time points throughout the first year post‐transplant in all three groups. GEE showed a significant reduction in weight‐adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group‐by‐time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.‐205_‐200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation.     

A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism

Abstract

Cytochrome P450 2E1 (CYP2E1) plays a vital role in drug-induced hepatotoxicity and cancers (e.g. lung and bladder cancer), since it is responsible for metabolizing a number of medications and environmental toxins to reactive intermediate metabolites. CYP2E1 was recently found to be the highest expressed CYP enzyme in human livers using a proteomics approach, and CYP2E1-related toxicity is strongly associated with its protein level that shows significant inter-individual variability related to ethnicity, age, and sex. Furthermore, the expression of CYP2E1 demonstrates regulation by extensive genetic polymorphism, endogenous hormones, cytokines, xenobiotics, and varying pathological states. Over the past decade, the knowledge of pharmacology, toxicology, and biology about CYP2E1 has grown remarkably, but the research progress has yet to be summarized. This study presents a timely systematic review on CYP2E1’s xenobiotic metabolism, genetic polymorphism, and inhibitors, with the focus on their clinical relevance for the efficacy and toxicity of various CYP2E1 substrates. Moreover, several knowledge gaps have been identified towards fully understanding the potential interactions among different CYP2E1 substrates in clinical settings. Through in-depth analyses of these knowns and unknowns, we expect this review will aid in future drug development and improve management of CYP2E1 related clinical toxicity.     

MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus).

We used proximal tubules isolated from the killifish, Fundulus heteroclitus, to examine the effect of environmentally relevant, sublethal levels of arsenic on the function and expression of MRP2, an ABC transporter that transports xenobiotics into urine, including arsenic-glutathione conjugates. Exposure of fish to arsenic as sodium arsenite (4-14 days) increased both MRP2 expression in the apical membrane of proximal tubules and MRP2-mediated transport activity. The level of MRP2 mRNA was not affected, suggesting a posttranslational mechanism of action. Acute exposure of proximal tubules isolated from control fish to 75-375 ppb arsenic decreased mitochondrial function (inner membrane electrical potential). However, in tubules from fish that were preexposed to arsenic (4-14 days), no such effect on mitochondrial function was observed. Thus, chronic in vivo exposure to arsenic induces mechanisms that protect proximal tubules during subsequent arsenic exposure. Upregulation of MRP2 expression and activity is one likely contributing factor.     

ROLE OF HEPATIC FATTY ACID:COENZYME A LIGASES IN THE METABOLISM OF XENOBIOTIC CARBOXYLIC ACIDS

1. Formation of acyl-coenzymes (Co)A occurs as an obligatory step in the metabolism of a variety of endogenous substrates, including fatty acids. The reaction is catalysed by ATP-dependent acid:CoA ligases (EC 6.2.1.1-2.1.3; AMP forming), classified on the basis of their ability to conjugate saturated fatty acids of differing chain lengths, short (C₂-C₄), medium (C₄-C₁₂) and long (C₁₀-C₂₂). The enzymes are located in various cell compartments (cytosol, smooth endoplasmic reticulum, mitochondria and peroxisomes) and exhibit wide tissue distribution, with highest activity associated with liver and adipose tissue. 2. Formation of acyl-CoA is not unique to endogenous substrates, but also occurs as an obligatory step in the metabolism of some xenobiotic carboxylic acids. The mitochondrial medium-chain CoA ligase is principally associated with metabolism via amino acid conjugation and activates substrates such as benzoic and salicylic acids. Although amino acid conjugation was previously considered an a priori route of metabolism for xenobiotic-CoA, it is now recognized that these highly reactive and potentially toxic intermediates function as alternative substrates in pathways of intermediary metabolism, particularly those associated with lipid biosyntheses. 3. In addition to a role in fatty acid metabolism, the hepatic microsomal and peroxisomal long-chain-CoA-ligases have been implicated in the formation of the acyl-CoA thioesters of a variety of hypolipidaemic and peroxisome proliferating agents (e.g. cloflbric acid) and of the r (-)-enantiomers of the commonly used 2-arylpropionic acid non-steroidal anti-inflammatory drugs (e.g. ibuprofen). In vitro kinetic studies using rat hepatic microsomes and peroxisomes have alluded to the possibility of xenobiotic-CoA ligase multiplicity. Although cDNA encoding a long-chain ligase have been isolated from rat and human liver, there is currently no molecular evidence of multiple isoforms. The gene has been localized to chromosome 4 and homology searches have revealed a significant similarity with enzymes of the luciferase family. 4. Increasing recognition that formation of a CoA conjugate increases chemical reactivity of xenobiotic carboxylic acids has led to an awareness that the relative activity, substrate specificity and intracellular location of the xenobiotic-CoA ligases may explain differences in toxicity. 5. Continued characterization of the human xenobiotic-CoA ligases in terms of substrate/inhibitor profiles and regulation, will allow a greater understanding of the role of these enzymes in the metabolism of carboxylic acids.     

Determination of Mercapturic Acid Excretions in Exposure Control to Toxicants

Abstract

Toxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.