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Biomedical subjects

L R Curtis

Publications and source records attributed to L R Curtis.

At least 19 recordsLinked to original sources
PubMed1995

Temperature-modulated incidence of aflatoxin B1-initiated liver cancer in rainbow trout.

Rainbow trout (initial weight of 4 or 5 g) were acclimated at a cool, 11.0 degrees C (C), a warm, 18.0 degrees C (W), or an intermediate temperature 14.5 degrees C (I) for 1 month. There was a slight difference in hepatic microsomal content of one of six cytochrome P450 isozymes between acclimation groups. Monounsaturated fatty acids in hepatic phosphotidylethanolamine but not phosphotidylcholine increased at lower acclimation temperatures. Saturated fatty acid content decreased with temperature for both phospholipid classes. Fish were exposed to 0.08-0.12 ppm waterborne aflatoxin B1 (AFB1) for 30 min at respective acclimation temperatures or after acute temperature shifts (24 hr) and reared for 9 months at C, I, or W. With exposure concentrations which delivered equivalent target organ doses, trout acclimated, exposed, and reared at C, I, or W had liver tumor incidences of 4, 35, and 61%, respectively. The average number of tumors per liver increased from 1.25-1.34 at C to 2.46-2.66 at W. There were no temperature-dependent differences in tumor diameter. When C- and W-acclimated fish were AFB1 exposed and reared at I, tumor incidence was 12.5% for W-I-shifted fish and 26.5% for C-I-shifted fish. This was consistent with previous work which demonstrated acute downward temperature shift reduced [3H]AFB1 adduction to hepatic DNA. Tumor incidence and multiplicity data suggested manipulation of temperature permitted selective modulation of cancer initiation and promotion in rainbow trout.

Aflatoxin B1↗
PubMed1995

In vitro and in vivo temperature modulation of hepatic metabolism and DNA adduction of aflatoxin B1 in rainbow trout.

Alterations in membrane lipid composition during temperature acclimation of poikilotherms is hypothesized to compensate for direct effects of temperature on membrane fluidity. Temperature also influences disposition and actions of some xenobiotics. This suggests the potential for complex interactions between temperature and metabolism of chemical carcinogens. Whole livers and hepatic microsomes from rainbow trout acclimated at 18 degrees C have more saturated fatty acids and less mono- and polyunsaturated fatty acids than those from fish acclimated at 10 degrees C. Such changes are consistent with a role for membrane lipid fluidity in temperature compensation. When 10 and 18 degrees C acclimated fish are ip injected with 0.4 mg/kg [3H]aflatoxin B1 (AFB1) at their respective acclimation temperatures, hepatic disposition of AFB1, DNA adduction, and biliary metabolites are similar. An acute shift of 18 degrees C acclimated trout to 14 degrees C reduces [3H]AFB-DNA adduct formation, while [3H]AFB1 adduction after acute shift of 10 degrees C acclimated fish to 14 degrees C is no different than in non-shifted fish. Hepatic microsomes isolated from 10 or 18 degrees C acclimated trout, incubated with 10 microM [3H]AFB1 and calf thymus DNA between 6 and 22 degrees C exhibit no differences in the "break points" of Arrhenius plots (16 degrees C in both groups). There is, however, more in vitro DNA adduction of [3H]AFB1 by microsomes from 18 degrees C acclimated fish, a difference abolished by 0.5 mM alpha-naphthoflavone (ANF). These results suggest that temperature acclimation of trout differentially modifies activities of cytochrome P-450 isozymes. When assayed at respective acclimation temperatures, hepatic cytosol from 18 degrees C fish produces more aflatoxicol, a detoxication product of AFB1, than cytosol from 10 degree C fish. Therefore, this soluble enzyme does not exhibit ideal temperature compensation. Such temperature-induced differences in microsomal cytochrome P-450 isozymes and cytosolic dehydrogenase partially explain temperature-modulated AFB1 genotoxicity.

Acclimatization↗
PubMed1994

Distribution of chlordecone to liver plasma membranes and recovery from hepatobiliary dysfunction in rats.

Chlordecone (CD) impairs biliary excretion of organic anions (including phenolphthalein glucuronide (PG), imipramine polar metabolites, and taurocholate) without evidence of hepatocellular necrosis in rats. In this study we investigated the hypothesis that CD-induced hepatobiliary dysfunction is dependent on CD concentration in liver plasma membranes where it inhibits active transport in vitro. Rats were treated by gavage (0 or 60 mg CD/kg in corn oil) 24 or 72 h prior to bile duct cannulation. Biliary excretion of PG, a marker of hepatic organic anion transport, and [14C]mannitol, a marker of passive transcellular permeability, was determined. Biliary excretion of PG decreased approximately 25% in rats 24 h after CD treatment, however rats recovered control PG excretion rates 72 h after CD treatment. Recovery of PG excretion occurred despite higher liver homogenate [14C]CD concentrations at 72 h than at 24 h after [14C]CD treatment. Biliary clearance of [14C]mannitol decreased both 24 h and 72 h after treatment. Even though the amount of [14C]CD retained in the liver was greater at 72 h than at 24 h after treatment, the concentration of [14C]CD in isolated liver plasma membranes (LPM) was the same (3.5-3.9 nmol/mg protein) at both times. There was a significant reduction in 5'-nucleotidase activity of LPM at 24 h but not at 72 h after CD. This study demonstrated no correlation between recovery from CD-induced hepatobiliary dysfunction and whole liver accumulation. Altered subcellular [14C]CD distribution (reduced LPM-to-homogenate concentration ratio was coincident with recovery.

Animals↗
PubMed1994

Chlordecone pretreatment alters [14C]chlordecone and [14C]cholesterol transport kinetics in the perfused rat liver.

Previous work demonstrated that pretreatment of mice with low doses of the organochlorine insecticide chlordecone (CD) altered the tissue disposition of a subsequent [14C]CD or [14C]cholesterol challenge dose. The profile of these changes was consistent with the induction of a protein integral to hepatic CD/cholesterol turnover. The present study was undertaken to confirm similar in vivo effects in the rat and to analyze potential CD-induced changes in hepatic transport kinetics in the perfused rat liver. For in vivo experiments, male, Sprague-Dawley rats were treated with CD (5, 15, or 40 mg/kg) and challenged 3 or 7 days later with a 5 mg/kg [14C]CD tracer dose. Rats challenged 3 days after treatment and evaluated 16 hr later showed a dose-dependent decrease in hepatic [14C]CD relative to controls. This decrease could not be attributed to alterations in liver mass or total liver lipid. For kinetics studies, rats received 15 mg/kg CD and livers were perfused 3 days later. Following a brief (5-7 min) single-pass perfusion, the perfusate was replaced with recirculating buffer containing albumin-bound [3H]oleic acid or high-density lipoprotein-bound [14C]CD or [14C]cholesterol. Livers from pretreated animals had significantly decreased rates of [14C]CD and [14C]cholesterol uptake. Efflux of [14C]CD and biliary excretion of [14C]cholesterol were increased. No changes were observed in uptake or biliary excretion of [3H]oleic acid. SDS-PAGE of hepatic cytosol revealed an enhanced band intensity corresponding to a M(r) of 25,600 in livers from pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

7-Alkoxycoumarin O-Dealkylase↗
PubMed1994

2,2',4,4',5,5'- and 3,3',4,4',5,5'-hexachlorobiphenyl alteration of uterine progesterone and estrogen receptors coincides with embryotoxicity in mink (Mustela vision).

Female mink (Mustela vison) are highly sensitive to organochlorine (OC)-induced reproductive impairment. However, mechanisms of this reproductive toxicity are unknown. We have investigated the possible role of steroid receptors in embryotoxicity and reduced neonate weights. Anestrous, juvenile female mink and pregnant adult mink were exposed to 3,3',4,4',5,5'-hexachlorobiphenyl (3HCB), a coplanar polychlorinated biphenyl (PCB), or 2,2',4,4',5,5'-hexachlorobiphenyl (2HCB), a noncoplanar PCB congener. Both congeners impaired 17 beta-estradiol-stimulated (24 hr after ip administration of 100 micrograms E2 beta ip) up-regulation of uterine nuclear estrogen receptors (ERn) in anestrous mink. Embryotoxicity and reduced embryo growth were first observed 14 days after exposure to 0.4 mg 3HCB/kg > 0.8 mg 3HCB/kg > 20 mg 2HCB/kg. In pregnant mink, all 3HCB treatments significantly increased progesterone receptor dissociation constants (PR Kd). ER concentration and PR total receptor number (Rt) were increased by 20 mg 2HCB/kg > 0.8 mg 3HCB/kg, but were unaffected by 0.4 mg 3HCB/kg. Serum E2 beta was below assay detection limits. Progesterone (P) concentrations were increased by 2HCB, decreased by 0.8 mg 3HCB/kg, and unchanged by 0.4 mg 3HCB/kg. Hepatic cytochrome P450 (P450) was induced 1.8-fold in anestrous and 2.2-fold in pregnant mink by 3HCB. Ethoxyresorufin-O-deethylase (EROD) was induced 13- and 4-fold in anestrous and pregnant mink, respectively. 2HCB exposure resulted in decreased P450 concentration in anestrous juveniles, but had no effect on P450 during gestation or EROD activity at any time. We propose that embryotoxicity and retarded embryo growth result from impairment of PR function and that differences in the efficacy of HCB treatments are a result of their dose-dependent, partial estrogenic actions which increase PR Rt via up-regulation of ER.

Animals↗
PubMed1994

Novel mechanisms in chemically induced hepatotoxicity.

This review focuses on cellular events that modulate hepatotoxicity subsequent to initial liver insult. Cellular events that determine the nature and extent of hepatotoxic injury and the ultimate outcome of that injury are also discussed. The roles of cell types other than hepatocytes, hepatocyte organelle-specific processes, and regeneration in progression or recovery from liver injury are emphasized. Leukocyte activities are key events in two distinct hepatotoxicities. Neutrophil-mediated, periportal inflammation appears to play a primary role in progression of alpha-naphthylisothiocyanate-induced cholangiolitic hepatitis. However, a humorally mediated autoimmune response to protein adducts that occurs after anesthesia is critical in onset of halothane-induced hepatitis. New insights into specific events at the hepatocyte level are also emerging. Although reducing gap junctional communication between hepatocytes can protect against progression of liver injury, down-regulation of the subunit proteins (connexins) can isolate neoplastic cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced cell injury. In oxidative injury, a pH-mediated mitochondrial permeability transition causes mitochondrial uncoupling and ATP loss and leads to cell death. The ultimate outcome of hepatotoxic injury depends on the extent of tissue repair. Stimulation of tissue repair after a sublethal dose of CCl4 appears to be the central mechanism in protection against death from a subsequent large dose. Taken together, these examples illustrate the importance of events subsequent to initial liver injury as determinants of extent of liver damage.

1-Naphthylisothiocyanate↗
PubMed1992

Temperature-modulated aflatoxin B1 hepatic disposition and formation and persistence of DNA adducts in rainbow trout.

Previous work showed that the incidence of chemically induced tumors in fish increased with environmental temperature. The present study assessed genotoxicity as a mechanism to explain such results. Rainbow trout (2 g) were acclimated to 10 or 18 degrees C for 1 month and then immersed in 0.1 ppm [3H]aflatoxin B1 (AFB1) solutions for 30 min at their respective acclimation temperatures, or at 14 degrees C. The total radioactivity in liver immediately after immersions was 50% higher for 18- than 10 degrees C-acclimated and exposed fish. Conversely, adduction of [3H]AFB1 to hepatic DNA of 10 degrees C-acclimated fish was higher than that of 18 degrees C-acclimated fish after exposure. A similar DNA adduction result was observed after [3H]AFB1 immersion concentrations were varied to achieve similar hepatic [3H]AFB1 equivalents. After acute shifts in temperature (10 to 14 degrees C or 18 to 14 degrees C), no differences were found in hepatic [3H]AFB1 equivalents. However, adduction of [3H]AFB1 to hepatic DNA was higher for 10- than for 18 degrees C-acclimated fish 1 day after exposures at 14 degrees C. This was probably explained by effects of temperature acclimation on the status of the membrane-bound cytochrome P-450 system, affecting its competition with a detoxifying cytosolic enzyme. After [3H]AFB1 immersions at respective acclimation temperatures, or acute temperature shifts to 14 degrees C, DNA adducts were less persistent in fish maintained for 21 days at 18 degrees C than at 10 degrees C. Our data demonstrated that temperature-modulated AFB1 genotoxicity occurred via three mechanisms: hepatic disposition and formation and persistence of DNA adducts.

Aflatoxin B1↗
PubMed1990

Chlordecone impairs Na(+)-stimulated L-[3H]glutamate transport and mobility of 16-doxyl stearate in rat liver plasma membrane vesicles.

Chlordecone (CD) treatment of rat liver plasma membranes (LPM) provided in vitro evidence for mechanisms of in vivo liver dysfunction caused by CD. LPM preparations enriched 14- to 19-fold in the bile canalicular markers gamma-glutamyl transpeptidase, alkaline phosphatase, and leucine aminopeptidase were isolated from male Sprague-Dawley rats. CD inhibited the bile canalicular-specific active transport of Na(+)-stimulated L-[3H]glutamate in LPM vesicles. CD (0.08 and 0.5 mumol/mg protein) reduced both the initial velocity and the maximum level of Na(+)-stimulated L-[3H]glutamate uptake without significantly reducing Na(+)-independent uptake. In vitro treatment of LPM with CD (0.2-1.0 mumols/mg protein) also reduced the mobility of a 16-doxyl stearate spin label probe in a concentration-dependent manner. No change in mobility was apparent at CD concentrations below 0.2 mumol/mg protein. These results demonstrated that CD impaired a bile canalicular-specific transport system and induced liver plasma membrane perturbation. Na(+)-stimulated L-[3H]glutamate uptake was more sensitive to CD than was detectable immobilization of the spin label probe.

Animals↗
PubMed1990

Biliary excretion appears rate limiting for hepatic elimination of benzo[a]pyrene by temperature-acclimated rainbow trout.

Previous work demonstrated that mixed function oxidase activities of hepatic microsomes from cold- and warm-acclimated rainbow trout were similar when assayed at temperatures to which fish were acclimated. This "ideal temperature compensation" was partially explained by constitutive differences in microsomes. In the work reported here, rainbow trout were acclimated at 10 or 18 degrees C for 4 weeks and then ip injected with 10 mumol [3H] or [14C]benzo[a]pyrene (BP)/kg in one of two temperature regimens. First, fish were acclimated and exposed at the same temperature and killed after 4, 24, or 48 hr. Concentrations of [3H]BP equivalents in liver, bile, and fat but not in plasma, muscle, intestine, gill, or kidney increased with time. There were no differences in hexane or ethyl acetate extractable [3H] or [14C]BP tissue concentrations in 10 and 18 degrees C-acclimated fish exposed at their acclimation temperatures. At 24 hr after injection, biliary excretion of [3H]BP equivalents was about twofold higher at 18 degrees C than at 10 degrees C. Therefore, warmer temperature stimulated biliary excretion without a marked effect on in vivo BP metabolism. In the second regimen, 10 and 18 degrees C-acclimated fish were shifted to 14 degrees C, injected with [3H] or [14C]BP 1 hr later, and killed after an additional 24 hr. There were no differences in tissue concentrations of total [3H]BP equivalents between acclimation groups at 14 degrees C. However, the biliary concentration of [14C]BP not extracted by ethyl acetate was significantly higher in bile from 10 degrees C-acclimated fish than from 18 degrees C-acclimated fish when both groups were exposed at 14 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Acclimatization↗
PubMed1990

2,3,7,8-Tetrachlorodibenzo-p-dioxin pretreatment of female mice altered tissue distribution but not hepatic metabolism of a subsequent dose.

Lipid partitioning of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inadequately explains its tissue distribution since higher concentrations occur in liver than fat except at high doses. This study provides in vivo evidence that an inducible, saturable system plays a predominant role in disposition of [14C]TCDD in female mice at doses between 5 and 20 micrograms/kg. Female C57BL/6J mice were gavaged with 0, 5, or 15 micrograms TCDD/kg, received a subsequent gavage of 5 or 20 micrograms [14C]TCDD after 6 days, and were killed 1 day later. In mice pretreated with 5 and 15 micrograms TCDD/kg and subsequently dosed with 20 micrograms [14C]TCDD/kg, liver weight and [14C]TCDD concentration increased. Total liver [14C]TCDD burden increased about 50% in both pretreatment groups. Concentrations of [14C]TCDD in kidney, fat, heart, lung, gastrointestinal tract, but not plasma or splenic lymphocytes, decreased in a reciprocal manner. Alterations in absorption, concentrations of polar metabolites of [14C]TCDD in liver, and hepatic lipid content failed to explain these results. About 97% of hepatic 14C was hexane extractable. HPLC of this extract indicated [14C]TCDD was the only significant nonpolar form of radiolabel in liver. In mice pretreated with 5 micrograms TCDD/kg and subsequently dosed with 5 micrograms [14C]TCDD/kg, a more marked pretreatment disposition response was observed. These results are consistent with a predominant role for an inducible, high affinity, low capacity system in whole animal pharmacokinetics of TCDD.

Animals↗
PubMed1990

The effect of thermal acclimation on the activity of arylhydrocarbon hydroxylase in rainbow trout (Oncorhynchus mykiss).

1. The possibility that temperature acclimation (to 10 or 18 degrees C for 28 days) would alter the cytochromes P-450 of rainbow trout was addressed. 2. The specific content of LM4b (P-450 IA1), the trout isozyme responsible for activation of polynuclear aromatic hydrocarbons, was lower in 18 degrees C fish than it was in 10 degrees C fish. 3. Kinetic analysis of aryl hydrocarbon hydroxylase indicated that, while thermal acclimation caused no change in Vmax, it lowered the apparent Km of this enzyme for benzo[a]pyrene when assayed at acutely shifted temperatures. 4. Thermal acclimation of fish may have significance when feral populations are subjected to acute temperature shifts.

Acclimatization↗
PubMed1989

Elevation of sex steroids and inhibition of UDP-glucuronyltransferase are out of phase during gonadal maturation in the common carp.

1. Plasma sex steroid concentrations, onset of gonadal maturation, and hepatic microsomal UDP-glucuronyltransferase (UDPGT) activities were followed under natural temperature and photoperiod in outdoor tanks, and under controlled laboratory temperature and photoperiod regimens in common carp (Cyprinus carpio). 2. Decreased activity of UDPGT was out of phase with elevations in plasma testosterone and 17 beta-estradiol during gonadal maturation. 3. Injection of pituitary extract induced final gonadal maturation and transient elevations (within 24 hr) of both plasma sex steroid concentrations and UDPGT activities. 4. There were no simple relationships between plasma sex steroid concentrations and activity of hepatic microsomal UDPGT in common carp.

Animals↗
PubMed1989

Libido, menopause, and estrogen replacement therapy.

Patients may be embarrassed to communicate their concerns regarding a decrease in sexual desire to their physician, let alone request treatment. Drs Beard and Curtis recommend that patients be asked specific questions to elicit symptoms of sexual dysfunction. They outline a program of hormone replacement therapy for women who have sexual dysfunction secondary to genitourinary atrophy and for those whose loss of libido is secondary to declining levels of estrogen.

Estrogens↗
PubMed1988

Chlordecone is a potent in vitro inhibitor of oligomycin-insensitive Mg2+ -ATPase of rat bile canaliculi-enriched fraction.

The oligomycin-insensitive Mg2+ -ATPase (OIMATPase) of rat bile canaliculi-enriched fraction (BCEF) was inhibited by chlordecone (CD) in vitro (IC-50 = 25 microM). Kinetic analysis indicated noncompetitive inhibition. Inhibition of OIMATPase by filipin but not by atractyloside verified plasma membrane origin of activity. The cholestatic agents alpha-naphthyl isothiocyanate (ANIT) and taurolithocholate (TLC) decreased OIMATPase activity at in vitro concentrations of 33 and 162 microM, while taurocholate (a choleretic bile salt), ethynylestradiol, and manganese did not. Cholestatic drugs with primary intracellular sites of action (colchicine and phalloidin) were ineffective OIMATPase inhibitors in this concentration range. Inhibition of OIMATPase by N-ethylmaleimide (NEM) and dicyclohexylcarbodiimide (DCCD) indicated some H+ -ATPase activity in BCEF. In vitro sensitivity of OIMATPase of BCEF to CD, ANIT, and TLC suggested the bile canaliculus as a subcellular-level target for their cholestatic actions.

Animals↗