Liver response tests. III. Liver enlargement and stimulation of microsomal processing enzyme activity

Gilbert, D.A.; Golberg, L.

doi:10.1016/s0015-6264(65)80129-8

Cited by 213 publications

(36 citation statements)

References 29 publications

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“…The rat and dog have a longer hepatic residence time, at peak concentrations, compared to humans (Table 5), making the livers of these species more vulnerable to chemical injury. Liver enlargement accompanied by induction of biotransformation enzymes has been found to be elicited by numerous xenobiotics (27,29,32,48,85,110), notably polycyclic aromatic hydrocarbons, barbiturates, butylated hydroxytoluene , and polychlorinated biphenyls. Such liver enlargement and increased LBR can result from both hypertrophy and hyperplasia of hepatocytes.…”

Section: Hepatic Adaptive and Adverse Effects Adaptationmentioning

confidence: 99%

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

2002

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Exposure of experimental animals to biologically effective levels of chemicals, either endogenou s or exogenous , the latter of either synthetic or natural origin, elicits a response(s) that re ects the diverse ways in which the various units of organization of an organism deal with chemical perturbation. For some chemicals, an initial response constitutes an adaptive effect that maintains homeostasis. Disruption of this equilibrium at any level of organization leads to an adverse effect, or toxicity. The livers of laboratory animals and humans, like other organs, undergo programmed phases of growth and development , characterized by proliferation followed by differentiation. With organ maturity, the process of differentiation leads to the commitment of differentiated cells to constitutive functions that maintain homeostasis and to specialized functions that serve organismal needs. In the mature livers of all species, proliferation of all cell types subsides to a low level. Thus, the mature liver consists of 2 types of cells: intermediate cells, the hepatocytes , which replicate infrequentl y, but can respond to signals for replication, and replicating cells, the stem cells, endothelial, Kupffer, and stellate cells (Ito or pericytes), bile duct epithelium, and granular lymphocyte s (pit cells). Quanti able alterations or effects at the molecular level underlie alterations at the organelle level, which in turn lead to alterations at the cellular level, which can ultimately be manifested as a change in the whole organism. Alterations can be quantal (binary), either all or none, as with cell replication, cell necrosis or apoptosis, and cell differentiation, which take place at the cellular level. They can also be graded or continuous (nonbinary ), as with enzyme induction, organelle hypertrophy, and extracellular matrix elaboration, occurring either at the intra-or extra (supra) cellular level. Any quanti able change induced in the function or structure of a cell or tissue constitutes a response or effect. Each of the several types of cell in the liver responds to a given stimulus according to its localization and function. Generally, renewing cells are more vulnerable to chemical injury than intermediate cells, which are largely quiescent. Hepatic adaptive responses usually involve actions of the chemical on cellular regulatory pathways, often receptor mediated, leading to changes in gene expression and ultimately alteration of the metabolome. The response is directed toward maintaining homeostasis through modulation of various cellular and extracellular functions. At all levels of organization, adaptive responses are bene cial in that they enhance the capacity of all units to respond to chemical induced stress, are reversible and preserve viability. Such adaptation at subtoxic exposures is also referred to as hormesis. In contrast, adverse or toxic effects in the liver often involve chemical reaction with cellular macromolecules and produce disruption of homeostasis. Such effects diminish the capacity for...

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Section: Hepatic Adaptive and Adverse Effects Adaptationmentioning

confidence: 99%

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

2002

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“…The fact that after more than 50 years of debate (Gilbert and Golberg 1965;Rowe et al 1959;Weil and McCollister 1963) the issue remains as contentious as ever prompted the European Society of Toxicologic Pathology (ESTP) to convene an expert opinion group to discuss the current state of the science. The purpose of the workshop was to discuss the significance of hepatocellular hypertrophy in rodents, define more clearly when adaptive responses become adverse, and understand the long-term consequences of hepatocellular hypertrophy in order to guide scientific opinion for risk assessment in man and dose setting for longer term animal studies.…”

Section: Introductionmentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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“…BHA Administration of BHA to mice has little or no effect on numerous other monooxygenase activities of hepatic microsomes (11,15,17), although ring hydroxylation of aniline is markedly enhanced (11). Liver microsomes from BHA-fed mice also produce altered patterns of metabolites from benzo[a]pyrene in vitro.…”

mentioning

confidence: 99%

Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

Benson¹,

Hunkeler²,

Talalay³

1980

Proc. Natl. Acad. Sci. U.S.A.

635

338

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2(3)tert-Butyl4hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarolinhibited NAD(P)HL quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.21 activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones an may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protectie effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.The widely used antioxidant food additive 2(3)-tert-butyl-4-hydroxyanisole (BHA) has a number of interesting and potentially important pharmacological properties. BHA Administration of BHA to mice has little or no effect on numerous other monooxygenase activities of hepatic microsomes (11,15,17), although ring hydroxylation of aniline is markedly enhanced (11). Liver microsomes from BHA-fed mice also produce altered patterns of metabolites from benzo[a]pyrene in vitro. Lam and Wattenberg (18) observed decreased epoxidation and increased formation of 3-hydroxybenzo[a]pyrene relative to controls, and these changes were accompanied by a 50% decrease in the binding of metabolites to DNA (19,20).The NADH-and NADPH-linked quinone oxidoreductase here called quinone reductase has also been designated variously as menadione reductase, DT-diaphorase, NAD(P)H dehydrogenase, and vitamin K reductase (21). Recent studies have shown that rat liver cytosol azoreductase activity for methyl red also reflects the action of quinone reductase (22, 23). Unusual features of this flavoprotein enzyme include: (i) comparable reaction with NADH and NADPH (24-26); (ti) potent and specific inhibition, in competition with reduced nicotinamide nucleotides, by dicoumarol and related vitamin K antagonists (24, 27); (iii) reversible stimulation of activity of the soluble cytosolic quinone reductase by serum albumin, neutral phospholipids, and a number of detergents (24,26,27); and (iv) broad specificity for a variety of hydrophobic quinones, including benzoquinones, na...

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Liver response tests. III. Liver enlargement and stimulation of microsomal processing enzyme activity

Cited by 213 publications

References 29 publications

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

Liver Hypertrophy

Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

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