Expression of the cytochrome P4502e and 2B gene families in the lungs and livers of nonpregnant, pregnant, and fetal hamsters

Miller, Mark Steven; Warner, Steven P.; Jorquera, Rossana; Castonguay, André; Schüller, Hildegard M.

doi:10.1016/0006-2952(92)90418-i

Cited by 19 publications

(7 citation statements)

References 19 publications

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“…This is the ®rst report of the biotransformation of benzene in the immature. The enzymes in the sucklings involved in the formation of the benzene metabolites are unknown but are likely to include CYP2E1, in view of the reported expression and activity of the enzyme in fetuses and newborns of experimental animals, including rats (Raucy and Carpenter 1993) and hamsters (Miller et al 1992). These observations contrast with the reported absence of the enzyme in fetal and neonatal rats in other studies (Hong et al 1987;Umeno et al 1988).…”

Section: Discussioncontrasting

confidence: 47%

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Iba

Ghosal

Snyder

2001

Archives of Toxicology

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Lactating adult female mice treated with a single dose of 880 mg/kg i.p. [14C]benzene, and their 2-day-old sucklings similarly treated or nursed by their treated dams were compared in terms of their ability to metabolize benzene to urinary products or reactive intermediates as assessed by covalently-bound benzene derivatives in whole blood or liver DNA. Six metabolite fractions were identified in the urine of sucklings by high performance liquid chromatographic (HPLC) analysis at 5 h following intraperitoneal (direct) treatment with benzene. Three of the metabolite fractions co-chromatographed with authentic phenol, phenyl glucuronide, and muconic acid, and contributed 11, 6.9 and 0.6%, respectively, to the total urinary benzene metabolites. Two of the fractions were unidentified. The sixth and most polar fraction consisted of multiple metabolites, 21% of which were conjugates, and accounted for 72% of the total urinary metabolites. A similar metabolite profile was observed in 24-h urine samples from treated dams with the exception that one of the unidentified fractions in the sucklings was absent and levels of the metabolites were quantitatively higher than those observed in sucklings 5 h following their treatment with benzene. Furthermore, 78% of the most polar fraction from the dams consisted of conjugates compared with 21% of that from the sucklings. The metabolite pattern in urine of sucklings nursed by treated dams was qualitatively similar to, but quantitatively different from the pattern in treated dams. Five hours following intraperitoneal treatment with benzene, covalent binding of the compound to DNA (expressed as pmol benzene equivalents/mg DNA) in sucklings was slightly higher in whole blood (1.15+/-0.07) than in liver (0.77+/-0.07), whereas in the dam, it was slightly lower in whole blood (0.88+/-0.48) than in liver (1.63+/-0.61). Twenty four hours following benzene exposure in sucklings of benzene-treated dams, DNA binding by the compound in whole blood (3.85+/-1.05) and liver (0.11+/-0.03) was higher and lower, respectively than the binding observed in benzene-injected sucklings 5 h following the injection. Our results show that excretable as well as reactive metabolites of benzene are formed substantially by the neonatal mouse, and that the extent of bioactivation of the compound is comparable in the adult and the suckling mouse. The results show also that sucklings of benzene-exposed mothers are exposed to substantial levels of the compound and are potentially susceptible to its toxic effects.

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Section: Discussioncontrasting

confidence: 47%

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Iba

Ghosal

Snyder

2001

Archives of Toxicology

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“…Neither CYP2E1 nor 1A2 were significantly induced by TS which indicates that fetal inductory mechanisms are functional but not yet sensitive for TS compounds in the first case, or they are immature, in the latter case. It should be pointed out that in some studies authors did not find the constitutive mRNA, apoprotein, and catalytic activity of CYP2E1 in the fetal rat liver, 2E1 protein in fetal hamster liver and lung (Miller et al 1992), and 2E1/E2mRNAs in the fetal rabbit liver and lung (Peng et al 1991) suggesting that CYP2E1 and E2 genes are activated within hours or days after birth in a species-specific manner (Wu and Cederbaum 1993). An importance of this developmental gene activation is probably implicated not only in the initiation of xenobiotic metabolism, but also in morpho-and embryogenesis during pregnancy.…”

Section: Discussionmentioning

confidence: 96%

“…CYPs change their profile during ontogenesis because of hormone regulation, diet, different rates of mammalian organ development and regulatory mechanisms of individual CYP expressions, and the influence of exogenous modulators (Waxman and Chang 1995). Fetal or neonatal exposure to carcinogens coexisting with developmental changes in the profile of P450s can significantly affect the sensitivity of humans and animals to P450-activated metabolites of drugs and procarcinogens, and may account for a significant number of tumors that occur later in adult life (Miller et al 1992).…”

Section: Introductionmentioning

confidence: 99%

Tobacco smoke-dependent changes in cytochrome�P450 1A1, 1A2, and 2E1 protein expressions in fetuses, newborns, pregnant rats, and human placenta

et al. 2004

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Tobacco smoke (TS) was described as a mixture of numerous cytochrome P450 (P450) substrates, inducers, and inhibitors. These inducers and inhibitors may modify drug clearance and xenobiotic or endogenous metabolism affecting P450s expression. In the present study, the effect of gestation and TS on: (1) cytochrome P450 CYP1A1, CYP1A2, and CYP2E1 protein expressions, and (2) cytochrome P450-linked microsomal enzyme activities, were studied in fetal rat liver, rat, and human placenta and in newborn and adult rat hepatic and extrahepatic tissues. Non-pregnant and pregnant 4-month-old female Wistar rats were exposed to TS (500, 1,000, or 1,500 mg carbon monoxide per m(3) air) in a toxicological chamber for 3 weeks (6 h daily, 5 days weekly). Human placentas were sampled from non-smoking, passive smoking, or active smoking primiparas. The efficacy of exposure was assessed by measuring urine cotinine levels. The TS-dependent inductory effect on the expression of CYP1A1 and 1A2 and related monooxygenase activities, and the inhibitory/inductory effect on CYP2E1 expression in rat tissues were observed. Pregnancy was associated with decreased levels of constitutive CYP1A1 and 2E1 in hepatic and extrahepatic tissues, TS-inducible CYP1A2 expression in the liver, and CYP1A1 expression in lungs and heart, but had no inhibitory effect on TS-inducible CYP1A1 and 2E1 expression, EROD, and P450-cooperated enzyme activities in the liver, kidney, and, in the latter case, in the heart. The presence of TS-induced CYP1A1 protein was confirmed in rat and human placenta and showed in newborn liver and lungs. CYP1A2 and 2E1 proteins were detectable in fetal rat liver. It was concluded that the expression of CYP1A1, 1A2, and 2E1, which metabolize some drugs and activate carcinogens, is controlled by age-, pregnancy-, and tissue-specific regulatory mechanisms in rats. Gestational differences in the regulation of expression of CYP1A subfamily members are not excluded. CYP1A1 and 2E1, but not CYP1A2 inductory mechanisms seem to be functional in fetal liver at day 21 of pregnancy but they appeared to be uninducible under a TS exposure. In TS-exposed pregnant females and fetuses the effects of metabolic activation of CYP1A1 and 1A2 substrates might be reduced because of lower CYP expressions or poor induction, respectively.

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“…Physiological changes are known to occur during pregnancy (e.g., the degree of binding to plasma proteins, hepatic metabolism) (Krauer, 1987). Studies comparing the hepatic microsomal metabolism in virgin, pregnant, and lactating rats or hamsters have shown that the levels of hepatic cytochrome P450 2E, (or related) were decreased in pregnant animals, especially in late pregnancy Miller et al, 1992;Casazza et al, 1994;Kim, 1995). Changes in the metabolism of DMF might contribute to the differences observed.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of N,N-Dimethylformamide Administered to Pregnant Rats

et al. 1997

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Expression of the cytochrome P4502e and 2B gene families in the lungs and livers of nonpregnant, pregnant, and fetal hamsters

Cited by 19 publications

References 19 publications

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Tobacco smoke-dependent changes in cytochrome�P450 1A1, 1A2, and 2E1 protein expressions in fetuses, newborns, pregnant rats, and human placenta

Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of N,N-Dimethylformamide Administered to Pregnant Rats

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