Sex, organ and species specific bioactivation of chloromethane by cytochrome P4502E1.
1. In the male mouse, chloromethane produces renal tumours after inhalation, and tumours were not seen in the female mouse and in both sexes of rat exposed under identical conditions. 2. Cytochrome P4502E1 present in kidney microsomes from the male mouse oxidized chloromethane to formaldehyde, and the amount of formaldehyde formed was dependent on the hormonal status of the animals and correlated well with the ability of the microsomes to oxidize chlorzoxazone, a specific substrate for cytochrome P4502E1. In kidney microsomes from the female mouse, significantly lower rates of oxidation of chloromethane and chlorzoxazone were observed; oxidation could be induced by testosterone pretreatment of the female. 3. In liver microsomes from both sexes of mouse, the rates of oxidation of chloromethane and chlorzoxazone were two-fold higher than in kidney microsomes from the male, however, no sex differences in the rates of oxidation were observed. 4. The rates of oxidation in mouse liver microsomes for both substrates could be markedly increased by pretreatment with the cytochrome P4502E1 inducer ethanol. 5. Kidney microsomes from both sexes of rat did not catalyze the formation of detectable concentrations of formaldehyde from chloromethane and exhibited only low rates of chlorzoxazone oxidation; in liver microsomes of both sexes of rat an ethanol-inducible oxidation of chloromethane and chlorzoxazone was observed.
Dekant
W
W
Institut für Toxikologie, Universität Würzburg, Germany.
Frischmann
C
C
Speerschneider
P
P
D000818:Animals; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000201:enzymology; D008297:Male; D008737:Methyl Chloride / Q000493:pharmacokinetics*; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013045:Species Specificity
D003577:Cytochrome P-450 Enzyme System; D008737:Methyl Chloride; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating