Thermolabile hemoglobin formation by 2-cyanaziridine derivatives.
The erythrocyte toxicity of imexone, azimexone, ciamexone, and its derivatives was assessed by means of the thermolabile hemoglobin formation test. After administration of doses up to 500 mg/kg to mice, imexone had no effect, whereas in accordance with previous studies azimexone strongly and ciamexone moderately enhanced thermolabile hemoglobin formation. With regard to the derivatives (metabolites) of ciamexone, the alcohol was as active as ciamexone itself, whereas ciamexone aldehyde gave a weak reaction. Both ciamexone acid and ciamexone-cysteine had no influence. Demethyl ciamexone, however, was more toxic than ciamexone, further indicating that the metabolic oxidation of the methyl group represents a detoxifying step. In contrast to the in vivo results, after incubation with blood samples solely imexone (in the range of mg/ml blood) but none of the other 2-cyanaziridines enhanced thermolabile globin formation. Preincubation of imexone with cysteine inhibited this effect. The results are discussed in view of the hypothesis that binding of the nitrile group of the 2-cyanaziridines to mercapto groups of proteins precedes their biological effects.
Isert
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B
Institut für Pharmakologie und Toxikologie, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Germany.
Schulte
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S
Mengel
K
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Friedberg
K D
KD
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001388:Aziridines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006588:Hexanones / Q000008:administration & dosage / Q000633:toxicity*; D006358:Hot Temperature; D007155:Immunologic Factors / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009391:Nephelometry and Turbidimetry; D010108:Oxyhemoglobins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D001388:Aziridines; D006454:Hemoglobins; D006588:Hexanones; D007155:Immunologic Factors; D010108:Oxyhemoglobins; C035520:ciamexon; C016866:azimexon; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one