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66966 
Journal Article 
Metabolism of 4,4'-methylene-bis-chloroaniline (MOCA) by rats in vivo and formation of N-hydroxy MOCA by rat and human liver microsomes 
Morton, KC; Lee, MS; Siedlik, P; Chapman, R 
1988 
Yes 
Carcinogenesis
ISSN: 0143-3334
EISSN: 1460-2180 
NIOSH/00180843 
9 
5 
731-739 
English 
3365833 
WOS:A1988N325900007 
The metabolism of 4,4'-methylene-bis-2-chloroaniline (101144) (MOCA) in rats in-vivo was studied and compared with the metabolism of MOCA by rat and human liver microsomal enzymes in-vitro. Male CD-rats were given 50mg/kg carbon-14 labeled MOCA by stomach tube once daily for 4 days and sacrificed 36 hours later. No more than 0.2 percent of the MOCA was recovered unchanged in urine. Enzymatic hydrolysis indicated the presence of glucuronide and sulfate conjugates. In bile, the predominant metabolite was the mono-N-glucuronide of MOCA. Following incubation of radioactive MOCA with fortified rat liver microsomes, N-hydroxylation of MOCA occurred at 335 picomoles per minute per milligram (pmol/min/mg) of microsomal protein, compared to 230 and 765pmol/min/mg for human liver microsomes from two different patients. Rat microsomes and the two preparations of human microsomes formed the 5-hydroxy metabolite at rates of 92, 7, and 35pmol/min/mg. Rates of formation for the benzhydrol derivative were 82, 60, and 160pmol/min/mg, respectively. Pretreatment of the rat microsome donors with phenobarbital enhanced all three rates by four to eight times. Pretreatment also enhanced the formation of partially characterized polar derivatives, representing 50 to 100 percent of the benzhydrol derivative in control or pretreated animals. The authors conclude that rats metabolize MOCA extensively, with oxidative attack occurring at the nitrogen, methylene bridge, and on the rings, and that scission at the methylene bridge also occurs. They further conclude that in human liver microsomes N-hydroxylation is the predominant reaction, suggesting that MOCA may be a human carcinogen since N-hydroxylation is known to be of significance in arylamine carcinogenesis. 
metabolism; in vivo; microsomes; 4,4'-methylene-bis-2-chloroaniline; N-hydroxy-4,4'-methylene-bis-2-chloroaniline; Toxicology Abstracts; X 24153:Metabolism