Effect of chronic hypoxia on detoxication enzymes in rat liver

Xiaoqin Shan, Yee Aw Tak Yee Aw, Elizabeth R. Smith, Magnus Ingelman-Sundberg, Bengt Mannervik, Takashi Iyanagi, Dean P. Jones

Research output: Contribution to journalArticle

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Abstract

Studies were performed to determine the effects of chronic hypoxia on enzymes that catalyze various detoxication reactions. Rats were exposed to room air or 10.5% O2 for 10 days, and microsomes and postmicrosomal supernatants were isolated from liver. Detoxication enzyme activities were measured by radiochemical and spectrophotometric assays, and immunoreactive protein amounts were measured by Western blot analysis. Total cytochrome P450, as measured by the CO-difference spectrum, and activities of Superoxide dismutase (EC 1.15.1.1), epoxide hydrolase (EC 4.2.1.63), catalase (EC 1.11.1.6), glutathione disulfide reductase (EC 1.6.4.2), and glutathione (GSH) S-transferase (EC 2.5.1.18) were not affected by this extent of hypoxia. In contrast, 10 days of hypoxia decreased activities or immunoreactivities (% of aerobic) of GSH peroxidase (EC 1.11.1.9) (54%), cytochrome P450EtOH2 (42%), CYP3A1 (53%), sulfotransferase (EC 2.8.2.1) (77%) and UDP-glucuronosyltransferase (EC 2.4.1.17) (65%). Activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), an important enzyme in NADPH production was also decreased to 56% of the aerobic value, but Western blot analysis showed that the amount of protein reactive with antibodies to glucose-6-phosphate dehydrogenase was not affected by hypoxia. Thus, hypoxia may decrease activity of enzymes by regulatory mechanisms even though the amount of immuno-detectable enzyme is unchanged. Liver cells isolated from rats exposed to hypoxia also gave lower GSH synthetic rates than cells from normoxic rats. This result, together with the effect of hypoxia on glucose-6-phosphate dehydrogenase, indicates that the GSH supply for GSH-dependent detoxication reactions may be limited due to chronic hypoxia. To test directly whether chronic hypoxia increased sensitivity to a compound normally detoxified by a GSH-dependent reaction, sensitivity to (tert-butyl hydroperoxide (t-BuOOH) of hepatocytes from rats exposed to in vivo hypoxia was compared to that from normoxic rats. The results showed that the cells from the hypoxic rats were much more sensitive to injury. Taken together, these results suggest that decreases in amounts and/or activities of detoxication enzymes during chronic hypoxia may result in increased susceptibility of cells to chemical injury.

Original languageEnglish
Pages (from-to)2421-2426
Number of pages6
JournalBiochemical Pharmacology
Volume43
Issue number11
DOIs
StatePublished - Jun 9 1992
Externally publishedYes

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Liver
Rats
Glucosephosphate Dehydrogenase
Enzymes
tert-Butylhydroperoxide
Epoxide Hydrolases
Sulfotransferases
Glucuronosyltransferase
Glutathione Reductase
Enzyme activity
Carbon Monoxide
Cytochromes
Transferases
NADP
Catalase
Cytochrome P-450 Enzyme System
Peroxidase
Superoxide Dismutase
Glutathione
Hypoxia

ASJC Scopus subject areas

  • Pharmacology

Cite this

Shan, X., Tak Yee Aw, Y. A., Smith, E. R., Ingelman-Sundberg, M., Mannervik, B., Iyanagi, T., & Jones, D. P. (1992). Effect of chronic hypoxia on detoxication enzymes in rat liver. Biochemical Pharmacology, 43(11), 2421-2426. https://doi.org/10.1016/0006-2952(92)90322-A

Effect of chronic hypoxia on detoxication enzymes in rat liver. / Shan, Xiaoqin; Tak Yee Aw, Yee Aw; Smith, Elizabeth R.; Ingelman-Sundberg, Magnus; Mannervik, Bengt; Iyanagi, Takashi; Jones, Dean P.

In: Biochemical Pharmacology, Vol. 43, No. 11, 09.06.1992, p. 2421-2426.

Research output: Contribution to journalArticle

Shan, X, Tak Yee Aw, YA, Smith, ER, Ingelman-Sundberg, M, Mannervik, B, Iyanagi, T & Jones, DP 1992, 'Effect of chronic hypoxia on detoxication enzymes in rat liver', Biochemical Pharmacology, vol. 43, no. 11, pp. 2421-2426. https://doi.org/10.1016/0006-2952(92)90322-A
Shan X, Tak Yee Aw YA, Smith ER, Ingelman-Sundberg M, Mannervik B, Iyanagi T et al. Effect of chronic hypoxia on detoxication enzymes in rat liver. Biochemical Pharmacology. 1992 Jun 9;43(11):2421-2426. https://doi.org/10.1016/0006-2952(92)90322-A
Shan, Xiaoqin ; Tak Yee Aw, Yee Aw ; Smith, Elizabeth R. ; Ingelman-Sundberg, Magnus ; Mannervik, Bengt ; Iyanagi, Takashi ; Jones, Dean P. / Effect of chronic hypoxia on detoxication enzymes in rat liver. In: Biochemical Pharmacology. 1992 ; Vol. 43, No. 11. pp. 2421-2426.
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