Metabolic activation of 4-ipomeanol by avian tissue microsomes

doi:10.1016/0041-008X(82)90361-1

Toxicology and Applied Pharmacology

Volume 65, Issue 1, August 1982, Pages 53-62

https://doi.org/10.1016/0041-008X(82)90361-1 Get rights and content

Abstract

The formation of highly reactive metabolites from 4-ipomeanol, a selective lung toxin in rodents and other mammals and a potent hepatotoxin in birds, was studied in tissues from roosters and Japanese quail in vitro. Consistent with previous in vivo studies on the target organ selectivity for covalent binding and toxicity of 4-ipomeanol metabolites in birds, the rates of reactive metabolite formation were very high in bird liver microsomes compared to avian pulmonary or renal microsomes where this activity was relatively very low or absent. The formation of reactive 4-ipomeanol metabolites in quail lung and liver microsomes was enzyme-mediated and dependent upon cytochrome P-450 monooxygenases. The covalent binding of 4-ipomeanol metabolites to microsomal protein was strongly inhibited by boiling the microsomes, by deleting the NADPH generating system, or by incubation in a CO:O₂ atmosphere. Incubation of quail liver or lung microsomes, NADPH, and reduced glutathione resulted in low levels of covalent binding and in two water-soluble glutathione conjugates which had identical high-pressure liquid chromatographic characteristics to those produced in similar incubations with rat lung or liver microsomes. The K_m for 4-ipomeanol covalent binding was nearly fourfold lower in quail liver as compared with quail lung microsomes while the V_max was eight times higher in liver than lung; these kinetic results were in sharp contrast to those obtained previously in similar studies with rat microsome preparations, where the pulmonary system was much more active. These results indicate the potential value of in vitro investigations in evaluating biochemical mechanisms underlying target tissue selectivity of toxic damage by xenobiotics acting via a highly reactive metabolite(s) produced in situ.

References (17)

A.R. Buckpitt et al.
In vivo studies on the target tissue metabolism, glutathione depletion, covalent binding, and toxicity of 4-ipomeanol in birds, species deficient in pulmonary enzymes for metabolic activation
Toxicol. Appl. Pharmacol.
(1982)
J.S. Dutcher et al.
Species and strain differences in target organ alkylation and toxicity by 4-ipomeanol; predictive value of covalent binding in studies of target organ toxicities by reactive metabolites
Biochem. Pharmacol.
(1979)
Y. Gutman et al.
Liver N-demethylating activity: Temperature effects and phenobarbital induction in different species
Biochem. Pharmacol.
(1971)
O. Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
T. Omura et al.
The carbon monoxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature
J. Biol. Chem.
(1964)
D.S.P. Patterson et al.
Effect of phenobarbital pretreatment on the in vitro metabolism of aflatoxin and aniline by duck and rat livers
Biochem. Pharmacol.
(1971)
M. Sifri et al.
Comparative effects of p,p-DDT and pentobarbital on hepatic microsomal enzymes in young quail, chicks and ducklings
Comp. Biochem. Physiol.
(1975)
C.A. Williams et al.
Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver
J. Biol. Chem.
(1962)

There are more references available in the full text version of this article.

Cited by (21)

Metabolic Activation and Toxicities of Furanoterpenoids
2016, Advances in Molecular Toxicology
Citation Excerpt :
Boyd and coworkers demonstrated that 4-IPO was activated preferentially in the lung of rats, rabbits, female mice, guinea pigs, and dogs [72]. Dogs treated with 4-IPO exhibit severe pulmonary injury, including capillary congestion, severe acute inflammation of alveoli and bronchioles, alveolar cell necrosis, proteinaceous alveolar exudates, and so on [64,73–75]. When different rabbit lung cell types were exposed to radiolabeled 4-IPO, nonciliated bronchiolar epithelial (Clara) cells presented the strongest radioactivity, indicating that the pulmonary toxicity is due to highly tissue-selective activation of 4-IPO by Clara cells, where pulmonary P450 enzymes are expressed at their highest levels [73,76].
This chapter introduces the bioactivation and toxicity of furanoterpenoids, particularly their hepatotoxicity. It starts with a brief description of biosynthesis of furanoterpenoids, followed by mechanisms of metabolic activation of furan-containing compounds and the interactions of reactive metabolites of furanoids with proteins. A total of five furanoterpenoids, i.e., 4-ipomeanol, teucrin A, diosbulbin B, 8-epidiosbulbin E acetate, and toosendanin, are discussed as examples. The chapter covers (1) the natural source and toxicities of the furanoterpenoids; (2) identification of reactive metabolites and major cytochromes P450 involved in the metabolic activation of the furan-containing compounds; and (3) protein modifications induced by the reactive metabolites of the furanoids. It also describes a newly developed approach to screen potentially harmful furan-containing compounds from complicated mixtures.
Metabolism of new anticancer agents
1989, Pharmacology and Therapeutics
Pulmonary toxicity of 4-ipomeanol
1989, Pharmacology and Therapeutics
Systematically applied chemicals that damage lung tissue
1985, Toxicology
A large, and increasing number of drugs and chemicals have been found which are toxic to lung following systemic administration. These agents damage lung tissue specifically, or in addition to damage to other tissues. Mechanisms explaining the pulmonary damage produced by some lung toxins have been uncovered. These include concentration of the agent within lung, the absence of adequate pulmonary detoxication systems, and bioactivation to a toxic species within specific lung cells or at distant sites followed by transport to the lung. The basic biochemical lesions underlying lung damage, responses of individual lung cells and pulmonary repair processes to the toxic agent, and species and age differences in susceptibility to lung damage have not, however, been well defined for most lung toxins. This review describes the information available on pulmonary biochemical and pathological changes associated with some of these lung-toxic agents. In addition, mechanisms proposed to explain the lung damage are discussed. The agents covered include: paraquat, the thioureas, butylated hydroxytoluene, the trialkylphosphorothioates, various lung-toxic furans and anti-neoplastic agents, the pyrrolizidine alkaloids, metals and organometallic compounds, amphiphilic agents, hydrocarbons, oleic acid, 3-methylindole, and diabetogenic agents. Detailed reviews on the overall toxicity of many of these agents have been published elsewhere. This review concentrates on their pulmonary toxicity. Information is presented as an overview to illustrate both the extensive literature that is available and the important questions that remain to be answered about systemic chemicals that damage lung tissue.
Hepatic biotransformation in the buzzard (Buteo buteo) and the Japanese quail (Coturnix coturnix): Effect of PCBs
1985, Comparative Biochemistry and Physiology. Part C, Comparative
1. Hepatic biotransformation was studied in microsomal (cytochrome P-450-dependent monooxygenase activities) and cytosolic (glutathione S-transferase activitiesz) fractions from Japanese quail (Coturnix coturnix) and buzzard (Buteo buteo).
2. Monooxygenase activities were not very different apart from a high 7-ethoxycoumarin de-ethylase activity in quail as compared to buzzard.
3. Glutathione S-transferase activities were higher in quail than in buzzard.
4. DP₅ (a commercial mixture of PCBs containing 50% chlorine) produced a marked increase in monooxygenase activity from quail liver. In contrast, no induction was found in buzzard under the same conditions. Glutathione S-transferase activities were not modified in both species.
Differential induction of hepatic drug metabolizing enzymes in Japanese quail by 1,2,4-trichlorobenzene
1983, Toxicology
The effects of single oral administration of 1,2,4-trichlorobenzene (TCB), 200, 400, 800 or 1600 mg/kg, and of daily oral administration of TCB, 400 mg/kg, for 3 consecutive days, on components of the microsomal mono-oxygenase system, glutathione, and the activities of cytosolic glutathione S-transferase and microsomal epoxide hydrolase in Japanese quail liver were studied. Cytochromes P-450 and b₅ contents of liver microsomes and the activities of 7-ethoxyresorufin deethylase (7-ERD) and glutathione S-transferase were significantly increased 1 day after administration of single doses of TCB. Liver GSH and 7-ethoxycoumarin deethylase (7-ECD) activity were unchanged. Microsomal epoxide hydrolase activity was significantly decreased at TCB doses above 400 mg/kg. Increases in cytochromes and activities of 7-ERD and glutathione S-transferase were also seen following the 3-day administration of TCB, 400 mg/kg. In addition, liver GSH and the acitivity of NADPH-cytochrome c reductase were significantly increased whereas 7-ECD was significantly decreased by the 3-day treatment. These findings indicate that in Japanese quail, TCB is an inducer of 7-ERD and glutathione S-transferase but not of 7-ECD and epoxide hydrolase.

View all citing articles on Scopus

¹: Supported in part by NHLBI Postdoctoral Fellowship 1F32-HL05236. Present address: Department of Community and Environmental Medicine, University of California, Irvine, Calif. 92717.

View full text

Article preview

Toxicology and Applied Pharmacology

Abstract

References (17)

In vivo studies on the target tissue metabolism, glutathione depletion, covalent binding, and toxicity of 4-ipomeanol in birds, species deficient in pulmonary enzymes for metabolic activation

Toxicol. Appl. Pharmacol.

Species and strain differences in target organ alkylation and toxicity by 4-ipomeanol; predictive value of covalent binding in studies of target organ toxicities by reactive metabolites

Biochem. Pharmacol.

Liver N-demethylating activity: Temperature effects and phenobarbital induction in different species

Biochem. Pharmacol.

Protein measurement with the Folin phenol reagent

J. Biol. Chem.

The carbon monoxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature

J. Biol. Chem.

Effect of phenobarbital pretreatment on the in vitro metabolism of aflatoxin and aniline by duck and rat livers

Biochem. Pharmacol.

Comparative effects of p,p-DDT and pentobarbital on hepatic microsomal enzymes in young quail, chicks and ducklings

Comp. Biochem. Physiol.

Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver

J. Biol. Chem.

Cited by (21)

Metabolic Activation and Toxicities of Furanoterpenoids

Metabolism of new anticancer agents

Pulmonary toxicity of 4-ipomeanol

Systematically applied chemicals that damage lung tissue

Hepatic biotransformation in the buzzard (Buteo buteo) and the Japanese quail (Coturnix coturnix): Effect of PCBs

Differential induction of hepatic drug metabolizing enzymes in Japanese quail by 1,2,4-trichlorobenzene