Developmental changes in hepatic activation of dietary mutagens by mice

Brennan-Craddock, W.E.; Neale, S.; Mallett, A.K.; Rowland, Ian

doi:10.1016/0009-2797(89)90111-7

Cited by 11 publications

(3 citation statements)

References 27 publications

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“…A similar increase was observed in exposed groups between the 1-day and 1month mice, followed by a decrease in the 2year animals. As previously reported, methylene chloride metabolism via the MFO pathway occurs predominantly through the P4502E1 isozyme (31), and similar age-related changes in P4502E1 activity have been reported elsewhere (32)(33)(34). Using 7-ethoxycoumarin as a substrate for cytochrome P4502E1 (35), Stohs et al (32) reported a near 3-fold increase in liver 2E1 activity for female Swiss Webster mice between the ages of 1 month and 9 months; this increase was followed by a gradual decline in activity out to 18 months.…”

Section: Csupporting

confidence: 86%

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

Thomas

Yang

Morgan

et al. 1996

Environ Health Perspect

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During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vmaxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice while decreases in glutathione S-transferase (GST) rate constant (Kfc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent Vmaxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year Vmaxc is significantly smaller than the 1-month group (p < 0.001). Within group differences in median Kfc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001). Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461). As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation for toxicologic data and its application to risk assessment.ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 4.Figure 4.Figure 4.Figure 5.Figure 5.Figure 5.Figure 5.

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Section: Csupporting

confidence: 86%

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

Thomas

Yang

Morgan

et al. 1996

Environ Health Perspect

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“…A similar increase was observed in exposed groups between the 1-day and 1-month mice, followed by a decrease in the 2-year animals. As previously reported, methylene chloride metabolism via the MFO pathway occurs predominantly through the P4502E1 isozyme (31), and similar age-related changes in P4502E1 activity have been reported elsewhere (32)(33)(34) (33) found no significant change in P4502E1 activity with age. Although differences in the GSTdependent pathway were also observed between control and treated mice, the gasuptake system is not extremely sensitive to changes in Kf (2), and drawing conclusions as to the meaning of these differences are tenuous.…”

Section: Data Treatmentsupporting

confidence: 63%

PBPK Modeling/Monte Carlo Simulation of Methylene Chloride Kinetic Changes in Mice in Relation to Age and Acute, Subchronic, and Chronic Inhalation Exposure

Thomas¹,

Yang²,

Morgan³

et al. 1996

Environmental Health Perspectives

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“…A final example comes from a report that rats exposed to cyclamate from birth convert significantly higher levels of this chemi-cal to the suspect bladder carcinogen, cyclohexylamine, than d o their dams after treatment of both groups for 5 months (Renwick 1977). Studies of the influence of age on other enzymes have also been reported by a number of investigators on cytochrome P-450 activated enzymes (Brennan-Craddock et a[. 1989;Horbach et al 1992).…”

Section: Figsmentioning

confidence: 93%

Microbial succession and intestinal enzyme activities in the developing rat

Chang

Chadwick

Allison

et al. 1994

Journal of Applied Bacteriology

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The succession of gut bacteria and selected intestinal enzyme activities in developing 7-35-d-old rats was studied. Aerobes and anaerobes were identified as members of four broad major bacterial groups, i.e. Gram-positive rods, Gram-positive cocci, Gram-negative rods and obligate anaerobes. The enzyme activities of nitro and azo reductases, beta-glucuronidase, dechlorinase and dehydrochlorinase were determined by anaerobic incubation of intestinal homogenates with 3,4-dichloronitrobenzene, methyl orange, p-nitrophenyl-beta-D-glucuronide, and p,p'-DDT respectively. Nitroreductase and azo reductase activities increased significantly with the appearance of anaerobes in the large intestine. No increase in either nitroreductase or azo reductase activities in the small intestine was found. The early and high level of beta-glucuronidase activity in the small and large intestines coincided with high numbers of coliforms recovered in 7 and 14 d animals. Dehydrochlorinase activity appeared early but was undetectable at both 21 and 28 d. Its activity increased at 35 d. Dechlorinase activity was variable in development. The rapid changes in the microbial flora and intestinal enzyme activities may influence the susceptibility of pre-pubescent rats to a variety of toxicants. Therefore, age-dependent toxicity may be important in the risk assessment of some environmental chemicals.

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Developmental changes in hepatic activation of dietary mutagens by mice

Cited by 11 publications

References 27 publications

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

PBPK Modeling/Monte Carlo Simulation of Methylene Chloride Kinetic Changes in Mice in Relation to Age and Acute, Subchronic, and Chronic Inhalation Exposure

Microbial succession and intestinal enzyme activities in the developing rat

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