Comparative metabolism of ortho-phenylphenol in mouse, rat and man.
1. Ortho-phenylphenol (OPP) was well absorbed in the male B6C3F1 mouse, with 84 and 98% of the administered radioactivity recovered in the 0-48-h urine of animals administered a single oral dose of 15 or 800 mg/kg respectively. High absorption and rapid elimination were also seen in the female and male F344 rat with 86 and 89% respectively of a single oral dose (27-28 mg/kg) found in the urine in 24 h. OPP was also rapidly eliminated from human volunteers following dermal exposure for 8 h (0.006 mg/kg), with 99% of the absorbed dose in the urine in 48 h. 2. Sulphation of OPP was found to be the major metabolic pathway at low doses in all three species, accounting for 57, 82 and 69% of the urinary radioactivity in the male mouse (15 mg/kg, p.o.), male rat (28 mg/kg, p.o.) and male human volunteers (0.006 mg/kg, dermal). OPP-glucuronide was also present in all species, representing 29, 7 and 4% of the total urinary metabolites in the low dose groups of mouse, rat and human volunteers respectively. 3. Conjugates of 2-phenylhydroquinone (PHQ) in these single-dose studies accounted for 12, 5 and 15% of the dose in mouse, rat and human, respectively. Little or no free OPP was found in any species. No free PHQ or PBQ was found in the mouse, rat or human (LOD = 0.1-0.6%). 4. A novel metabolite, the sulphate conjugate of 2,4'-dihydroxybiphenyl, was identified in rat and man, comprising 3 and 13% of the low dose respectively. 5. Dose-dependent shifts in metabolism were seen in the mouse for conjugation of parent OPP, indicating saturation of the sulphation pathway. Dose-dependent increases in total PHQ were also observed in mouse. 6. This study was initiated to elucidate a mechanistic basis for the difference in carcinogenic potential for OPP between rat and mouse. However, the minor differences seen in the metabolism of OPP in these two species do not appear to account for the differences in urinary bladder toxicity and tumour response between mouse and rat.
Health and Environmental Research Laboratory, Dow Chemical Co., Midland, MI 48674, USA.
M J
MJ
Bartels
D A
DA
McNett
C
C
Timchalk
A L
AL
Mendrala
W R
WR
Christenson
G K
GK
Sangha
K A
KA
Brzak
S N
SN
Shabrang
D000818:Animals; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005965:Glucuronates / Q000652:urine; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D018629:Spectrometry, Mass, Secondary Ion
D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D002273:Carcinogens; D005965:Glucuronates; C004369:2-phenylphenol