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Featured researches published by Mont R. Juchau.


Life Sciences | 1979

Teratogenic bioactivation of cyclophosphamide in vitro

Alan G. Fantel; Jean C. Greenaway; Mont R. Juchau; Thomas H. Shepard

Abstract Day 10 rat embryos grown as cultured explants in vitro developed characteristic defects when culture media contained cyclophosphamide (6.25 micrograms per milliliter or more), an hepatic microsomal fraction, and cofactors for a monooxygenase system. Cyclophosphamide concentrations as high as 250 micrograms per milliliter were innocuous when either the microsomal material or cofactors were omitted from the medium. These experiments represent the first direct demonstration of bioactivation of a proteratogen.


Clinical Pharmacokinectics | 1980

Drug Metabolism by the Human Fetus

Mont R. Juchau; S. T. Chao; Curtis J. Omiecinski

SummaryA review of the literature that pertains to drug biotransformation in human fetal tissues reveals that, in spite of several publications in this comparatively new area of research, only very limited definitive information is currently available. The large majority of the studies performed have dealt with the cytochrome P-450-dependent microsomal mono-oxygenase systems and for several of the common drug metabolising reactions, very little or no data are available at this time. Some of the more important data that have emerged include observations that important bioactivation reactions can be demonstrated in human fetal tissues obtained during the period of late embryogenesis (high susceptibility to chemical dysmorphogenesis) and that the human fetal adrenal gland possesses considerable capacity to catalyse several important oxidation-reduction reactions.From the data available to date, it would appear that, in most instances, the biotransformation of drugs in the human embryo and fetus would not affect maternal plasma concentrations significantly. From the viewpoint of parameters of the pharmacokinetics of parent drug (or other xenobiotic) substrates under steady-state conditions, human fetal drug metabolism probably is of little consequence in most cases, although exceptions may exist. Pharmacokinetic parameters observed after isolated exposure, however, are very likely to be affected, perhaps markedly, in some instances.The demonstrated capacity of human prenatal tissues and cells to generate reactive intermediary metabolites, including those that produce mutations, has attracted the greatest attention recently. This capacity may be associated with extremely important adverse reactions to drugs and other environmental chemicals. Such adverse responses include transplacental mutagenesis, carcinogenesis, dysmorphogenesis, and perhaps several other undesirable effects. Although far from conclusive, the data tend to suggest that humans and subhuman primates may be more vulnerable than the smaller common experimental animals to the toxic effects of foreign organic chemicals during prenatal life. These factors should be weighed whenever exposure of pregnant women to such agents (e.g. via drug administration) is contemplated.


Toxicology and Applied Pharmacology | 1971

Human placental hydroxylation of 3,4-benzpyrene during early gestation and at term.

Mont R. Juchau

Benzpyrene hydroxylase activity in human placental tissues was investigated during early gestation (8–16 wk) in order to determine whether cigarette smoking would produce increased hydroxylation capacity at this gestational stage. Particulate subfractions of term placental homogenates from women who smoked cigarettes during pregnancy exhibited relatively high levels of enzymatic activity. At 8–10 wk gestation, however, levels of enzymatic activity in homogenates of human placenta or fetal livers were undetectable regardless of maternal smoking habits. At 11–13 wk gestation, very low levels of hydroxylase activity were observed in placentas of smokers, and slightly higher levels were apparent in smoker placentas at 14–16 wk gestation. Hydroxylating capacity of placental homogenates from nonsmokers was not detected at 8–16 wk gestation. Steroids synthesized by human placental tissues, i.e., β -estradiol, estrone, and progesterone, markedly inhibited the placental-catalyzed hydroxylation of benzpyrene. Cholesterol, dehydroepiandrosterone, testosterone, and androstenedione, which serve as substrates for other placental mixed-function oxidase systems, however, exhibited comparatively minor inhibitory effects. Similar effects of these and other steroids (methyltestosterone and pregenolone) were observed on the placental hydroxylase of 3-methyl-cholanthrene pretreated rats.


Life Sciences | 1990

Substrate specificities and functions of the P450 cytochromes

Mont R. Juchau

Currently, the major recognized biochemical functions of members of the large superfamily of P450 hemoproteins (referred to commonly as the cytochromes P450) include catalyses of the monooxygenations of a wide variety of endogenous and exogenous lipophilic chemicals. Substrates that have attracted the greatest attention thus far are steroids, fatty acids, eicosanoids, retinoids, other endogenous lipids, therapeutic agents, pesticides/herbicides, chemical carcinogens, industrial chemicals and other environmental contaminants and toxic xenobiotic organics of low molecular weight. Commonly, monooxygenation of such substrates results in the generation of metabolites capable of producing biological effects that are profoundly different (qualitatively as well as quantitatively) from those elicitable by the parent chemical per se. P45OXIX-dependent conversion of testosterone to estradiol-17 beta provides a dramatic example. Thus, these hemoproteins serve as extremely important but, as yet, largely unpredictable regulators of the biological effects producible by endobiotics as well as by xenobiotics. Current focus is on the identification and acquisition of sequence information on hereto unidentified and/or uncharacterized P450 isoforms and ascertainment of the specific functions of specific, individual isoforms. The regulation of quantities and activities of such isoforms in specific species/tissues, understandably, is also of great current interest. This interest has been further intensified by recent results indicating that substrate specificity associated with one P450 may not be the same as the corresponding isoform derived from a different animal species. Recent technological advances promise to greatly hasten the acquisition of knowledge concerning the functions of these important hemoproteins.


Bulletin of Environmental Contamination and Toxicology | 1974

Metabolism of 3,4-benzpyrene in rainbow trout (Salmo gairdneri)

M. G. Pedersen; W. K. Hershberger; Mont R. Juchau

Research report:biotransformation of 3,4-benzpyrene in various tissues of the rainbow trout is described. Incubation of 3,4-benzpyrenee with homogenates of various trout tissues shows that the liver, posterior kidney, and heart are capable of converting the substrate to its 8-hydroxy derivative. (2 graphs, 1 table)


Life Sciences | 1973

Drug biotransformation reactions in the human fetal adrenal gland

Mont R. Juchau; Mark G. Pedersen

Abstract Microsomal fractions of human fetal adrenal gland homogenates were found to contain large quantities of a carbon monoxide binding pigment which exhibited an absorption maximum between 446 and 448 nm. Human fetal liver microsomes exhibited similar spectral properties but the concentration of the pigment in the adrenal microsomes appeared to be at least one order of magnitude higher than that observed in fetal liver microsomes. Aryl hydrocarbon hydroxylase specific activities in fetal adrenal microsomes approached those observed in analagous preparations of adult rat livers. Fetal adrenal homogenates from humans and monkeys ( Macaca nemestrina ) also exhibited much higher specific activities with respect to aromatic nitro group and azo linkage reduction and p-hydroxylation of aniline. Comparisons of drug metabolic activities in fetal adrenal glands with activities observable in several other fetal and placental tissues were made in humans, monkeys and guinea pigs. None of the fetal or placental tissues studied appeared to contain significant aminopyrine N-demethylase activity.


Journal of Toxicology and Environmental Health | 1981

Further investigations of the capacity of polynuclear aromatic hydrocarbons to elicit atherosclerotic lesions.

James A. Bond; Allen M. Gown; Hsueh L. Yang; Earl P. Benditt; Mont R. Juchau

Treatment of chickens for up to 20 wk with varying doses (0.1-10 mg/kg) of benzo[a]pyrene (BaP) or 7,12-dimethylbenz[a]anthracene (DMBA) resulted in significant increases in incidence and size of atherosclerotic lesions at the two higher doses utilized (1 and 10 mg/kg). Maximal lesion formation for birds treated chronically with BaP occurred at 1 mg/kg, while development of lesions in birds treated with DMBA was roughly linear over the dose range tested. The largest doses of BaP or DMBA (10 mg/kg for 20 wk) produced the highest percentage of chickens with detectable lesions (75 and 89%, respectively). Lower doses of BaP or DMBA resulted in a smaller percentage of birds (per group) with lesions, and the lowest dose (0.1 mg/kg) produced no statistical increase in lesion incidence. At approximately equimolar doses, DMBA appeared to be more potent than BaP in enhancing the development of lesions in the chickens. Administration of a single dose of BaP or DMBA followed by weekly doses of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 wk did not result in enhancement of lesion formation over the respective controls. Blood cholesterol was not significantly altered after treatment of chickens with DMBA, BaP, or TPA.


Toxicology and Applied Pharmacology | 1987

Regulation of intracellular glutathione in rat embryos and visceral yolk sacs and its effect on 2-nitrosofluorene-induced malformations in the whole embryo culture system

Craig Harris; Moses J. Namkung; Mont R. Juchau

The dysmorphogenic effects of 2-nitrosofluorene (NF) in vitro were modulated in Day 10 rat embryos by agents which regulate intracellular glutathione (GSH) levels. The incidence of abnormal axial rotation caused by NF alone increased in a dose-dependent manner at NF concentrations in excess of 25 microM. No effects were observed at 15 microM NF and doses of 100 microM resulted in a 100% incidence of mortality. L-Buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH synthesis, produced malformations (50%) in embryos exposed to 15 microM NF but produced no additional effects on embryos at higher NF concentrations. BSO treatment alone resulted in a greater than 50% decrease in GSH content in visceral yolk sacs and had a lesser but likewise significant effect (15% decrease) on the GSH content of embryos. Protein content was inversely affected as embryonic levels were increased by 20% and yolk sac levels were unchanged. When BSO was added in combination with NF at the onset of the culture period, embryonic GSH decreased in a dose-dependent manner, suggesting a relatively low rate of embryonic GSH turnover that could be increased by addition of an exogenous substrate capable of forming adducts with and removing GSH from the cells. 2-Oxothiazolidine-4-carboxylate (OTC), a compound which is enzymatically modified to provide an additional source of intracellular cysteine and increase GSH synthesis, produced no significant changes in embryonic or yolk sac GSH when added alone to the culture medium. When OTC (5 mM) was added in combination with NF, however, NF-elicited malformations were eliminated. This was also the case at 100 microM NF in which OTC not only prevented malformations but completely protected embryos against the loss in viability. The GSH and protein levels were indistinguishable from controls when OTC and NF were added simultaneously except for the 41 microM NF dose at which a highly significant increase in both embryonic and yolk sac protein was observed. This study clearly demonstrates the potential importance of GSH in the modulation of chemical dysmorphogenesis and provides an important new tool for the study of mechanisms of developmental toxicity.


Biochemical Pharmacology | 1995

Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates.

Hao Chen; Moses J. Namkung; Mont R. Juchau

Catalysis of the oxidation of all-trans-retinol (vitamin A1) or of all-trans-retinal to all-trans-retinoic acid (all-trans-RA) by rat conceptal enzymes was investigated during organogenesis. Products of the reaction were identified and quantified with HPLC by comparing their elution times with those of authentic standard retinoids. Under the incubation and assay conditions utilized, all-trans-retinol and all-trans-retinal were converted to readily detectable quantities of all-trans-RA. Rat conceptal homogenates from gestational days 10.5, 11.5 and 12.5 each exhibited enzymatic activity for oxidation of all-trans-retinol and all-trans-retinal to all-trans-RA. Enzymatic catalysis was verified by showing that: (1) both reactions were coenzyme dependent; (2) the rates of reactions increased as concentrations of conceptal protein increased; (3) both reactions were abolished by heating the tissue homogenates (100 degrees, 5 min); and (4) both reactions exhibited substrate saturation. Under the same experimental conditions, formation of all-trans-RA from all-trans-retinol was much slower than from all-trans-retinal, suggesting that oxidation of all-trans-retinol to all-trans-retinal was the rate-limiting step for biotransformation of all-trans-retinol to all-trans-RA in embryonic tissues. When NAD or NADP were replaced by NADH or NADPH, the rate of oxidation of all-trans-retinol was reduced markedly, indicating that the reaction was catalyzed primarily by an NAD/NADP-dependent dehydrogenase(s). Carbon monoxide (CO:O2 = 90:10) did not inhibit the reaction. NAD appeared to be a more effective cofactor than NADP in catalyzing oxidation of all-trans-retinal to all-trans-RA. When NAD was omitted, formation of all-trans-RA from all-trans-retinal was reduced by approximately 55%. Replacing NAD by NADH or NADPH also reduced the conversion of all-trans-retinal to all-trans-RA by about 60%. These observations suggested at least two pathways for the generation of all-trans-RA from all-trans-retinal in embryos: oxidation catalyzed by an NAD/NADP-dependent dehydrogenase(s) and oxidation catalyzed by an oxidase(s) that did not require NAD, NADH, NADP or NADPH. Conversion of all-trans-retinol to all-trans-RA was inhibited strongly by low concentrations of citral, but not by high concentrations of sodium azide, 4-methylpyrazole, or metyrapone. Similarly, oxidation of all-trans-retinal was inhibited strongly by citral but not by metyrapone.(ABSTRACT TRUNCATED AT 400 WORDS)


Toxicology and Applied Pharmacology | 1985

Effects of 3-methylcholanthrene and phenobarbital on the capacity of embryos to bioactivate teratogens during organogenesis☆

Mont R. Juchau; Cecilia M. Giachelli; Alan G. Fantel; Jean C. Greenaway; Thomas H. Shepard; Elaine M. Faustman-Watts

Pregnant Sprague-Dawley rats were divided into four groups and given ip injections of 3-methylcholanthrene (MC) in corn oil, corn oil only, phenobarbital (PB) in Hanks balanced salt solution (HBSS), or HBSS only. Maternal animals were killed on Day 10 of gestation, and embryos from each group were explanted in medium containing cyclophosphamide (CP), 2-acetylaminofluorene (AAF), or dimethylsulfoxide vehicle. After a 24-hr culture period, embryos from dams treated with HBSS, corn oil, or PB/HBSS exhibited no increase in abnormalities (as compared with controls) when either CP or AAF were added to the media. However, embryos transplacentally preexposed to MC and subsequently treated during culturing with AAF (but not CP) exhibited striking increases in malformation incidence. Commonly observed malformations included abnormally open neural tubes, abnormal flexure rotation, and prosencephalic defects. Homogenates of Day 10 embryos transplacentally preexposed to MC exhibited readily measurable oxidative biotransformation of AAF as assessed with HPLC. Biotransformation of AAF by embryos from the other three groups was virtually undetectable. Incorporation of exogenously supplemented bioactivating systems from livers of mature animals indicated that postmitochondrial supernatant fractions (S-9) from male, MC-pretreated rats effectively catalyzed the conversion of AAF (but not CP) to embryotoxic metabolites. Conversely, hepatic S-9 from adult, male, PB-pretreated rats was highly effective in converting CP (but not AAF) to embryotoxic metabolites. The results indicated the inducerspecific occurrence of embryonic bioconversion of AAF to embryotoxic metabolites via MC-inducible, P-450-dependent, embryonic enzyme systems.

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Alan G. Fantel

University of Washington

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David L. Berry

University of Washington

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Hao Chen

University of Washington

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Qwihee P. Lee

University of Washington

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J. DiGiovanni

University of Washington

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T. J. Slaga

University of Washington

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Craig Harris

University of Washington

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