Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor
(PPAR
)
Tamie Nakajima6,
Yuji Kamijo1,
Nobuteru Usuda2,
Yan Liang2,
Yoshimitsu Fukushima,
Kiyokazu Kametani4,
Frank J. Gonzalez5 and
Toshifumi Aoyama3
1 Department of Hygiene, Second Department of Internal Medicine,
2 First Department of Anatomy,
3 Department of Aging Biochemistry and
4 General Research Laboratory, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan and
5 Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA
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Abstract
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The mechanism of trichloroethylene-induced liver peroxisome proliferation and the sex difference in response was investigated using wild-type Sv/129 and peroxisome proliferator-activated receptor
(PPAR
)-null mice. Trichloroethylene treatment (0.75 g/kg for 2 weeks by gavage) resulted in liver peroxisome proliferation in wild-type mice, but not in PPAR
-null mice, suggesting that trichloroethylene-induced peroxisome proliferation is primarily mediated by PPAR
. No remarkable sex difference was observed in induction of peroxisome proliferation, as measured morphologically, but a markedly higher induction of several enzymes and PPAR
protein and mRNA was found in males. On the other hand, trichloroethylene induced liver cytochrome P450 2E1, the principal enzyme responsible for metabolizing trichloroethylene to chloral hydrate, only in males, which resulted in similar expression levels in both sexes after the treatment. Trichloroethylene influenced neither the level of catalase, an enzyme involved in the reduction of oxidative stress, nor aldehyde dehydrogenase, the main enzyme catalyzing the conversion to trichloroacetic acid. These results suggest that trichloroethylene treatment causes a male-specific PPAR
-dependent increase in cellular oxidative stress.
Abbreviations: ALDH, aldehyde dehydrogenase; AOX, acyl-CoA oxidase; CTEII, cytosolic thioesterase II; CYP, cytochrome P450; DAB, 3,3'-diaminobenzidine; DBF, D-type (peroxisomal) bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), key enzyme of bile acid synthesis from cholesterol; PH, peroxisome bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase); PPAR
, peroxisome proliferator-activated receptor
; PT, peroxisomal thiolase; RXR
, retinoid X receptor
; TP
, trifunctional protein
subunit (long chain-specific hydratase + long chain-specific 3-hydroxyacyl-CoA dehydrogenase); TPß, long chain-specific 3-ketoacyl-CoA thiolase; VLACS, very long chain acyl-CoA synthetase.
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Introduction
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A number of rodent cancer bioassays have been carried out using trichloroethylene (1). In these studies, mouse liver tumors were most frequently reported (24). Tumors have been most frequently observed in both male and female Swiss and B6C3F1 mice, but not in NMRI mice. Interestingly, the incidence was greater in males than in females (5).
Trichloroethylene and its metabolite chloral hydrate are not considered to be direct acting carcinogens (6), but trichloroacetic acid, one of the major metabolites of trichloroethylene, is likely to be involved in carcinogenesis (7). Strain differences in the incidence of liver tumors induced by trichloroethylene is, therefore, thought to be dependent on differences in the rate of oxidation of trichloroethylene and the kinetic behavior of this metabolite. This is supported by studies in Swiss and B6C3F1 mice, where trichloroacetic acid accounted for 712% of the dose (8), whereas in NMRI mice this metabolite was only 0.1% of the dose (9). Further support for a mechanism of carcinogenesis involving trichloroethylene came from studies in which trichloroacetic acid induced exactly the same responses as trichloroethylene and caused liver tumors in mice at dose levels equivalent to the amount of trichloroacetic acid formed from trichloroethylene in vivo (6). On the other hand, the cause of the sex difference in hepatocarcinogenesis has not yet been fully understood.
Induction of peroxisome proliferation by trichloroethylene, which is thought to have a strong correlation with carcinogenesis, is likely to be mediated by peroxisome proliferator-activated receptor
(PPAR
) (10). Recently, a PPAR
-null mouse was used to demonstrate the role of PPAR
in hepatocarcinogenesis using the most potent experimental peroxisome proliferator Wy-14,643 (11). In the present paper, the mechanisms of trichloroethylene-induced liver peroxisome proliferation was investigated using the PPAR
-null mouse.
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Materials and methods
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Animals and trichloroethylene treatment
PPAR
-null mice on an Sv/129 genetic background were produced as described elsewhere (11). Wild-type Sv/129 mice were used as controls in all experiments. Male and female mice were mated and the young were housed together in a cage in a clean room with controlled temperature, relative humidity and light (12 h light/dark cycle). They were maintained on rodent chow and tap water ad libitum throughout the course of the experiment.
At 10 weeks of age, 12 male and female PPAR
-null and wild-type mice were divided into two groups, respectively: one group was treated with 0.75 g/kg (4 ml/kg corn oil) trichloroethylene daily for 2 weeks by gavage; the other was treated with the same amount of corn oil for 2 weeks (control group). All mice were killed at 10:00 a.m. the day after the last dose by CO2 asphyxiation. A small portion of the removed liver was cut up and used for histopathological investigations and the remaining part was homogenized in 10 mM potassium phosphate buffer (pH 7.4) containing 0.25 M sucrose.
Light and electron microscopy of peroxisomes
Liver peroxisome proliferation was evaluated morphologically using 3,3'-diaminobenzidine (DAB) staining according to the method of Novikoff and Goldfischer (12). Small pieces of liver from each mouse were fixed with 3% glutaraldehyde, 0.1 M cacodylateHCl, pH 7.2, for 2 h and rinsed in 7.5% sucrose at 4°C, prior to incubation for 60 min at 37°C in the DAB reaction medium (0.2% DAB tetrahydrochloride, 50 mM propanediol, pH 9.7, 5 mM KCN, 0.05% H2O2). After fixation in 1% OsO4, 0.1 M sodium phosphate, pH 7.4, for 1 h, the tissue was dehydrated with a graded series of ethanol and acetone and embedded in Epok 812 (Oken, Tokyo, Japan). Two micrometer sections were prepared, stained with 0.1% toluidine blue solution and subjected to photomicrography.
Sections (0.1 µm) prepared from the embedded liver were collected on grid meshes. After being stained with uranyl acetate and lead citrate, they were observed with a JEOL 100 CEX electron microscope at an accelerating voltage of 80 keV. Cytoplasmic areas of hepatocytes were photomicrographed at 10 000x and the volume density of peroxisomes (% of cytoplasm) was measured with a Luzex-III image analyzer (Nireco, Tokyo, Japan) in 15 micrographs of the pericentral area per liver (13). The resulting mean value was designated as the volume density of peroxisomes in the liver.
Analysis of ß-oxidation enzymes and cytochrome P450
Liver extracts were subjected to 10% SDSPAGE and transferred to nitrocellulose membranes. After blocking with 3% skim milk, the membranes were incubated with the primary antibody followed by alkaline phosphatase-conjugated goat anti-rabbit IgG (Jackson, West Grove). The primary polyclonal antibodies were prepared using purified acyl-CoA oxidase (AOX) (14), peroxisomal bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase) (PH) (15), peroxisomal thiolase (PT) (16), very long chain acyl-CoA synthetase (VLACS) (17), D-type peroxisomal bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase, key enzyme of bile acid synthesis from cholesterol) (DBF) (18), cytosolic thioesterase II (CTEII) (19), mitochondrial trifunctional protein
subunit (long chain-specific hydratase + long chain-specific 3-hydroxyacyl-CoA dehydrogenase) (TP
) (20), mitochondrial trifunctional protein ß subunit (long chain-specific 3-ketoacyl-CoA thiolase) (TPß) (20) and cytochrome P450 (CYP)2E1 (21), CYP1A1/1A2 (22) and CYP4A1 (23), respectively. Antibodies against ß-oxidation enzymes were kindly supplied by Dr T.Hashimoto (Shinshu University School of Medicine, Japan). The primary polyclonal antibodies to PPAR
(11) and retinoid X receptor
(RXR
) (Santa Cruz Biotechnology, Santa Cruz, CA), which dimerizes with a complex of PPAR
and peroxisome proliferator(s), were also used to elucidate the mechanism of sex differences in induction of the above enzymes by trichloroethylene. In the analysis of these receptors, blocking with 3% gelatin was used before reaction with the respective primary antibodies.
The signals obtained by immunoblot analysis were quantified by scanning densitometry and the means from the wild-type male mice of the control group, except for CTEII and CYP4A1, were assigned the value 1.0. In the case of CTEII and CYP4A1, the means from male wild-type mice treated with trichloroethylene were assigned the value 1.0.
mRNA analysis
mRNA analysis was performed by northern blotting. Total liver RNA was extracted, electrophoresed on 1.1 M formaldehyde-containing 1% agarose gels and transferred to nylon membranes (24). The membranes were incubated with a 32P-labeled PPAR
cDNA probe (25) and analyzed with a Fuji phosphorimager (Fuji Photo Film Co., Tokyo, Japan).
Assay of trichloroethylene-metabolizing enzymes
Trichloroethylene is primarily metabolized by hepatic CYP2E1 and CYP1A2 (26), followed by alcohol dehydrogenase, to produce trichloroethanol, and aldehyde dehydrogenase (ALDH), to trichloroacetic acid. The expression of CYP2E1 and CYP1A1/1A2 was analyzed by western blot analysis using liver microsomal fraction. Metabolism of chloral hydrate to trichloroacetic acid (total ALDH activity) in liver 700 g supernatant was examined by measuring the rate of NADH formation.
Statistics
Significance of differences for interactive effects of two factors (PPAR
gene and trichloroethylene treatment or gender and trichloroethylene treatment) was analyzed by two-way analysis of variance. Probability levels <0.05 were used as a criterion of significance.
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Results
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Liver weight
Trichloroethylene treatment did not alter body weight in any of the experimental groups (Table I
). The treatment, however, increased the liver/body ratio in all groups: the increase was most prominent in the wild-type male mice. These results indicate that the male wild-type gave a large hepatomegaly response to trichloroethylene treatment.
Light and electron microscopy of peroxisomes
Upon treatment with trichloroethylene, the numbers of peroxisomes in hepatocytes of wild-type mice increased, especially in the pericentral area of hepatic lobuli, to a similar extent in both males and females (Figure 1
): trichloroethylene treatment increased the volume density of peroxisomes 2-fold (Table II
). A change in peroxisomes in the periportal areas, however, was not evident (data not shown). In contrast, no increase was observed in PPAR
-null mice, similar to observations after Wy-14,643 treatment (11).

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Fig. 1. Light micrographs of liver tissues of wild-type and PPAR -null mice stained by the alkaline DAB reaction. Pictures of the pericentral area of hepatic lobuli are presented (x1000). Peroxisomes appear as dark stained particles. TRI, trichloroethylene.
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Table II. Volume density of peroxisomes in the liver pericentral area of male and female controls and trichloroethylene (TRI)-treated mice
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Expression of enzymes regulated by PPAR
Although no difference was seen in peroxisome proliferation induced by trichloroethylene treatment, expression of 10 enzymes known to be regulated by PPAR
(27) was examined in order to understand the relationship between peroxisome proliferation and enzyme induction. As shown in Figure 2
and Table III
, trichloroethylene treatment significantly increased the level of the liver peroxisomal enzymes (AOX, PH, PT, VLACS and DBF), a cytosolic enzyme (CTEII), the mitochondrial enzymes (TP
and TP
) and a microsomal enzyme (CYP4A1) in male wild-type mice. Surprisingly, these increases, except for slight elevations of PH and PT, were not observed in female wild-type mice. No increase in any of these enzymes was seen in male and female PPAR
-null mice treated with trichloroethylene, as expected. These results indicate that induction of nine of the enzymes is regulated by PPAR
and that the degree of induction is greater in male mice than in females. On the other hand, expression of catalase was nearly constant in all samples, suggesting that induction by trichloroethylene was independent of PPAR
.

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Fig. 2. Immunoblot analysis of selected ß-oxidation enzymes and P450s. Pooled liver cell lysate (8 and 20 µg protein for ß-oxidation enzymes and P450s, respectively) was subjected to electrophoresis and western immunobloting. TRI, trichloroethylene treatment; +, wild-type mice; , PPAR -null mice.
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Expression of trichloroethylene-metabolizing enzymes
Trichloroethylene-metabolizing enzymes were examined to investigate whether the poor induction of PPAR
-related enzymes (Table III
) by trichloroethylene in female mice is dependent upon the differences in expression of the metabolizing enzymes. As shown in Figure 2
and Table III
, liver CYP1A2 was decreased by treatment of both male and female wild-type mice. Liver CYP2E1 increased in male mice and was constant in females after treatment, which resulted in a similar expression level in both sexes (2.38 ± 0.39 in males and 1.84 ± 0.37 in females) after trichloroethylene treatment.
ALDH activity in the 700 g supernatant fraction was measured using chloral hydrate as a substrate (Table IV
). There were no obvious sex differences in activity following trichloroethylene treatment and activity was independent of PPAR
. These results suggest that trichloroethylene-metabolizing abilities in liver of males and females are similar to each other.
Expression of PPAR
and RXR
Transcriptional activation mediated by PPAR
and peroxisome proliferator-response elements is through dimerization of PPAR
with RXR
(11), therefore, expression levels of PPAR
and RXR
seem to relate to that of the target gene product. Hepatic levels of PPAR
and RXR
were analyzed by western blotting to determine whether the poor induction of PPAR
-related enzymes (Table III
) by trichloroethylene in female wild-type mice is due to a lower level of these receptors. There were no sex differences in the constitutive expression of either receptor (Figure 3A
). The level of PPAR
increased in both male wild-type mice (control versus trichloroethylene, 1.00 ± 0.20 versus 2.17 ± 0.24, P < 0.01) and females (0.95 ± 0.25 versus 1.44 ± 0.09, P < 0.05) on trichloroethylene treatment; induction was clearly greater in the former than in the latter (P < 0.05). The hepatic level of RXR
also increased in the same manner as that of PPAR
(control versus trichloroethylene, 1.00 ± 0.33 versus 1.92 ± 0.04 in males, P < 0.01; 0.81 ± 0.16 versus 1.14 ± 0.10 in females, P < 0.05; males versus females, P < 0.001). As indicated in Figure 3B
, induction of PPAR
mRNA by the treatment was much greater in males (2.6-fold) than in females (1.5-fold), which is compatible with the results at the protein level. Thus, simultaneous increases in the two nuclear receptors were observed at higher levels in male mice, which seems to cause the higher levels of induction of a series of enzymes (Figure 2
and Table III
).
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Discussion
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The present results clearly indicate that trichloroethylene causes liver peroxisome proliferation in both male and female mice through PPAR
. Although the extent of peroxisome proliferation was similar between the sexes, induction of PPAR
target gene products was significantly greater in males than in females. When using Wy-14,643, a potent activator of PPAR
, very high levels of peroxisome proliferation and enzyme induction were found (27), but no sex differences in extent of induction were observed (Aoyama et al., unpublished data). When using trichloroethylene in the present study, the levels of peroxisome proliferation and induction were lower than those using 0.1% Wy-14,643, which is compatible with the fact that trichloroacetic acid, a metabolite of trichloroethylene, seems to have a decreased ability to activate PPAR
. Peroxisome proliferation and induction of PPAR
target gene products may occur independently in spite of appearing simultaneously in vivo after the administration of peroxisome proliferators. Therefore, the ability of peroxisome proliferators to activate PPAR
may be an important determinant in understanding the sex difference in induction, i.e. trichloroethylene treatment may function differently in males and females due to a decreased ability of its metabolite to activate receptors such as PPAR
and RXR
in females. On the other hand, the levels of trichloroethylene-metabolizing enzymes in male and female mice were rather similar (Tables III and IV
) and administration of chloral hydrate produced similar responses in terms of induction as did trichloroethylene administration (Nakajima et al., unpublished data). Trichloroethylene metabolism therefore seems unimportant as a cause of the sex difference.
Several kinds of peroxisome proliferators are known to induce peroxisomal fatty acid ß-oxidation enzymes and liver tumors (2831). Trichloroethylene belongs to this type of peroxisome proliferator. Interestingly, liver tumor incidences induced by trichloroethylene are greater in males than in females (5). This sex difference seems to depend on a much greater increase in peroxisomal AOX, producing hydrogen peroxide through a reaction using molecular oxygen, in males (Figure 2
and Table III
), while the levels of hydrogen peroxide scavenger proteins (32), catalase (Table III
) and the activity of glutathione peroxidase (data not shown) remain constant in both males and females, suggesting that the increase in cellular oxidation stress occurs only in males. Humans are thought to be resistant to trichloroethylene because of lower blood levels of trichloroacetic acid (7), a lower liver content of PPAR
and, possibly, expression of abnormal isoforms of PPAR
(33). The risk based on trichloroethylene exposure may thereby be limited to rodents only.
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Acknowledgments
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This research was supported by a Special Research Grant (no. 11470095) from the Japan Ministry of Education, Science, Sports and Culture. The critical comments of Prof. E Johnson are also gratefully acknowledged.
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Notes
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6 To whom correspondence should be addressed Email: tnasu23{at}sch.md.shinshu-u.ac.jp 
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References
|
---|
-
ECETOC (1994) Trichloroethylene: Assessment of Human Carcinogenic Hazard, Technical Report no. 60. ECETOC, Brussels, Belgium.
-
Maotoni,C., Lefemine,G., Cotti,G. and Perino,G. (1988) Long-term carcinogenicity bioassays on trichloroethylene administration by inhalation to Sprague-Dawley rats and Swiss and B6C3F1 mice. Ann. N. Y. Acad. Sci., 534, 316342.[Abstract]
-
NCI (1996) Carcinogenesis Bioassay of Trichloroethylene, Technical Report Series no. 2. DHEW publication no. (NIH) 76-802 (1976). US Department of Health, Education and Welfare, Washington, DC.
-
NTP (1983) Carcinogenesis Bioassays of Trichloroethylene in F344 Rats and B6C3F1 Mice, NIH Publication no. 82-1799. US Department of Health and Human Service, Research Triangle Park, NC.
-
NTP (1990) Toxicology and Carcinogenesis Studies of Trichloroethylene (Without Epichlorohydrin) (CAS No. 79-01-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies), Technical Report Series no. 243, NIH Publication no. 90-1779. US Department of Health and Human Service, Research Triangle Park, NC.
-
Green,T. (1997) Trichloroethylene induced cancer in animals and its relevance to humans. J. Occup. Health, 39, 261273.[ISI]
-
Ashby,J., Brady,A., Elcombe,C.R., Elliott,B.M., Ishmael,J., Odum,J., Tugwood,J.D., Kettle,S. and Purchase,I.F. (1994) Mechanically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum. Exp. Toxicol., 13, 1117.[ISI]
-
Green,T. and Prout,M.S. (1985) Species differences in response to trichloroethylene. II. Biotransformation in rats and mice. Toxicol. Appl. Pharmacol., 79, 401411.[ISI][Medline]
-
Dekant,W., Metzler,M. and Henschler,D. (1984) Novel metabolites of trichloroethylene through dechlorination reactions in rats, mice and humans. Biochem. Pharmacol., 33, 20212027.[ISI][Medline]
-
Krey,G., Braissant,O., L'Horset,F., Kalkhoven,E., Perround,M., Parker,M.G. and Wahli,W. (1997) Fatty acids, eicosanoids and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol., 11, 779791.[Abstract/Free Full Text]
-
Lee,S.S., Pineau,T., Drago,J., Lee,E.J., Owens,J.W., Kroetz,D.L., Fernandez-Salguero,P.M., Westphal,H. and Gonzalez,F.J. (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol., 15, 30123022.[Abstract]
-
Novikoff,A.B. and Goldfischer,S. (1969) Visualization of peroxisomes (microbodies) and mitochondria with diaminobenzidine. J. Histochem. Cytochem., 17, 675680.[ISI][Medline]
-
Usuda,N., Reddy,M.K., Hashimoto,T., Rao,S. and Reddy,J.K. (1988) Tissue specificity and species differences in the distribution of urate oxidase in peroxisomes. Lab. Invest., 58, 100111.[ISI][Medline]
-
Osumi,T., Hashimoto,T. and Ui,N. (1980) Purification and properties of acyl-CoA oxidase from rat liver. J. Biochem. (Tokyo), 87, 17351746.[Abstract]
-
Osumi,T. and Hashimoto,T. (1980) Purification and properties of mitochondrial and peroxisomal 3-hydroxyacyl-CoA hydroxyacyl-CoA dehydrogenase from rat liver. Arch. Biochem. Biophys., 202, 372383.
-
Furuta,S., Miyazawa,S., Osumi,T., Hashimoto,T. and Ui,N. (1980) Properties of mitochondrial and peroxisomal enoyl-CoA hydratases from rat liver. J. Biochem. (Tokyo), 88, 10591070.[Abstract]
-
Uchiyama,A., Aoyama,T., Kamijo,K., Uchida,Y., Kondo,N., Orii,T. and Hashimoto,T. (1996) Molecular cloning of cDNA encoding rat very long-chain acyl-CoA synthetase. J. Biol. Chem., 271, 3036030365.[Abstract/Free Full Text]
-
Jiang,L.L., Miyazawa,S. and Hashimoto,T. (1996) Purification and properties of rat D-3-hydroxyacyl CoA dehydrogenase: D-3-hydroxyacyl-CoA dehydrogenase/D-3 hydroxyacyl-CoA hydroxyacyl-CoA dehydrogenase bifunctional protein. J. Biochem. (Tokyo), 120, 633641.[Abstract]
-
Miyazawa,S., Furuta,S. and Hashimoto,T. (1981) Induction of a novel long-chain acyl-CoA hydratase in rat liver by administration of peroxisome proliferators. Eur. J. Biochem., 117, 425430.[Abstract]
-
Uchida,Y., Izai,K., Orii,T. and Hashimoto,T. (1992) Novel fatty acid ß-oxidation enzymes in rat liver mitochondria: II. Purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein. J. Biol. Chem., 267, 10341041.[Abstract/Free Full Text]
-
Aoyama,T., Gelboin,H.V. and Gonzalez,F.J. (1990) Mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline by complementary DNA-expressed human liver P450. Cancer Res., 50, 20602063.[Abstract]
-
Aoyama,T., Yamano,S., Guzelian,P.S., Gelboin,H.V. and Gonzalez,F.J. (1990) Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin B1. Proc. Natl Acad. Sci. USA, 87, 47904793.[Abstract]
-
Aoyama,T., Hardwick,J.P., Imaoka,S., Funae,Y., Gelboin,H.V. and Gonzalez,F.J. (1990) Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the
-(
-1)-hydroxylation of fatty acids and the
-hydroxylation of prostaglandins E1 and F2
. J. Lipid Res., 31, 14771482.[Abstract]
-
Aoyama,T., Ueno,I., Kamijo,T. and Hashimoto,T. (1994) Rat very-long-chain acyl-CoA dehydrogenase, a novel mitochondrial acyl-CoA dehydrogenase gene product, is a rate-limiting enzyme in long-chain fatty acid ß-oxidation system. J. Biol. Chem., 269, 1908819094.[Abstract/Free Full Text]
-
Issemann,I. and Green,S. (1990) Activation of a member of the steroid hormone receptor super-family by peroxisome proliferators. Nature, 347, 645650.[ISI][Medline]
-
Nakajima,T., Wang,R.-S., Elovaara,E., Park,S.S., Gelboin,H.V. and Vainio,H. (1993) Cytochrome P450-related differences between rats and mice in the metabolism of benzene, toluene and trichloroethylene in liver microsomes. Biochem. Pharmacol., 45, 10791085[ISI][Medline]
-
Aoyama,T., Peters,J.M., Iritani,N., Nakajima,T., Furihata,K., Hashimoto,T. and Gonzalez,F.J. (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor
(PPAR
). J. Biol. Chem., 273, 56785684.[Abstract/Free Full Text]
-
Rao,M.S. and Reddy,J.K. (1991) An overview of peroxisome-induced hepatocarcinogenesis. Environ. Health Perspect., 93, 205209.[ISI][Medline]
-
Marsman,D.S. and Popp,J.A. (1994) Biological potential of basophilic hepatocellular foci and hepatic adenoma induced by peroxisome proliferator, WY-14,643. Carcinogenesis, 15, 111117.[Abstract]
-
Popp,J.A. and Cattley,R.C. (1992) Peroxisome proliferators as initiators and promoters of rodent hepatocarcinogenesis. In Gibson,G.G. and Lake,B.G. (eds) Monograph of Peroxisome Proliferation. Taylor and Francis, London, UK, pp. 653665.
-
Peters,J.M., Cattley,R.C. and Gonzalez,F.J. (1997) Role of PPAR
in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis, 18, 20292033.[Abstract]
-
Reddy,J.K. and Chu,R. (1996) Peroxisome proliferator-induced pleiotropic responses: pursuit of a phenomenon. Ann. N. Y. Acad. Sci., 804, 176201.[ISI][Medline]
-
Palmer,C.N., Hsu,M.H., Griffin,K.J., Raucy,J.L. and Johnson,E.F. (1998) Peroxisome proliferator activated receptor-alpha expression in human liver. Mol. Pharmacol., 53, 1422.[Abstract/Free Full Text]
Received May 21, 1999;
revised November 12, 1999;
accepted November 15, 1999.