Effect of phenethyl isothiocyanate on microsomal N-nitrosodimethylamine metabolism and other monooxygenase activities.
1. Phenethyl isothiocyanate (PEITC), a dietary compound derived from cruciferous vegetables, has previously been shown to decrease N-nitrosodimethylamine (NDMA)-induced methylation of hepatic DNA, apparently by inhibition of microsomal activation of the procarcinogen. 2. Using hepatic microsomes from acetone-treated rats, PEITC exhibited competitive inhibition of NDMA demethylase activity with an apparent Ki of 1 microM. In studies using a two-stage incubation protocol, the inhibition by PEITC was time- and metabolism-dependent. 3. Using control rat liver microsomes, PEITC selectively inhibited P450 IIE1-mediated NDMA-demethylase activity as compared to the demethylation of benzphetamine and ethylmorphine. 4. Pretreatment of rats with a single oral dose of PEITC (1 mmol/kg body wt) 24 h before killing caused a marked decrease in hepatic NDMA demethylase activity, but an 11-fold increase in 7-pentoxyresorufin O-dealkylase activity. These trends agreed with immunoblot analysis which indicated that PEITC was a suppressor of P450 IIE1 but an inducer of P450 IIB1. 5. The selective inhibition of P450 IIE1 activity and suppression of its level in microsomes indicates a role for PEITC as a chemopreventive agent against toxic or carcinogenic metabolites of this isozyme.
Ishizaki
H
H
Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855-0789.
Brady
J F
JF
Ning
S M
SM
Yang
C S
CS
D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D004128:Dimethylnitrosamine / Q000378:metabolism*; D066298:In Vitro Techniques; D017879:Isothiocyanates; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D013861:Thiocyanates / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D017879:Isothiocyanates; D013861:Thiocyanates; C058305:phenethyl isothiocyanate; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine