S. Ozawa et al., Metabolic activation of o-phenylphenol to a major cytotoxic metabolite, phenylhydroquinone: role of human CYP1A2 and rat CYP2C11/CYP2E1, XENOBIOTICA, 30(10), 2000, pp. 1005-1017
1. The in vitro metabolic activation of o-phenylphenol has been evaluated a
s yielding a toxic metabolite, 2,5-dihydroxybiphenyl (phenylhydroquinone),
by p-hydroxylation in liver microsomes of rat and human. The involvement of
rat CYP2C11, CYP2E1 and human CYP1A2 in the p-hydroxylation of o-phenylphe
nol is suggested.
2. 2,3- and phenylhydroquinone, which induced DNA single-strand scission in
the presence of 1 muM CuCl2, were the most cytotoxic chemicals examined to
cultured mammalian cell lines among o-phenylphenol, m-phenylphenol, p-phen
ylphenol, 2,2'-, 4,4'-, 2,3- and phenylhydroquinone.
3. Rat and human liver microsomes catalysed the formation of phenylhydroqui
none, but not 2,3-dihydroxybiphenyl, using o-phenylphenol as a substrate. A
higher rate of metabolic activation of o-phenylphenol was observed with li
vers of the male than the female rats by 5.6- and 2.6-fold respectively.
4. Inhibitory antibodies against the male-specific CYP2C11 inhibited hepati
c o-phenylphenol p-hydroxylation in the male F344 and Sprague-Dawley rat by
> 70%. Liver microsomes from the isoniazid-treated rats produced 1.8- and
3-fold induction of o-phenylphenol p-hydroxylation and chlorzoxazone 6-hydr
oxylation (a CYP2E1-dependent activity) respectively.
5. Human CYP1A2, expressed by baculovirus-mediated cDNA expression systems,
exhibited a remarkably higher capacity for o-phenylphenol p-hydroxylation
at concentrations of 5 (> 5-fold), 50 (> 2-fold) and 500 muM (> 2-fold) tha
n CYP2A, CYP2B, CYP2Cs, CYP2D6, CYP2E1 and CYP3A4 on the basis of pmol P450
.
6. Among various CYP inhibitors tested here, 7,8-benzoflavone and furafylli
ne, typical human CYP1A2 inhibitors, inhibited the microsomal p-hydroxylati
on of o-phenylphenol in human livers most potently by 70 and 50% respective
ly.
7. The results thus indicate the involvement of rat CYP2C11/CYP2E1 and huma
n CYP1A2 in the hepatic p-hydroxylation of o-phenylphenol.