US EPA

782811 

Journal Article 

Biphenyl metabolism in isolated rat hepatocytes: effect of induction and nature of the conjugates 

Wiebkin, P; Fry, JR; Jones, CA; Lowing, RK; Bridges, JW 

1978 

Yes 

Biochemical Pharmacology
ISSN: 0006-2952
EISSN: 1873-2968 

NIOSH/00167516 

27 

15 

1899-1907 

English 

708474 

10.1016/0006-2952(78)90003-5 

The metabolism of biphenyl (92524) was studied in isolated rat hepatocytes. Rats were pretreated with sodium-phenobarbitone (57307) (phenobarbitone) or 3-methylcholanthrene (56495) (MC) or left untreated. Approximately 20 hours later, they were killed, livers were removed, and hepatocytes were isolated. Hepatocytes were incubated with 70 micromolar (microM) biphenyl for up to 45 minutes (min). Aliquots were taken and analyzed for metabolites. Sulfate and glucuronide freely conjugated 4-hydroxybiphenyl (92693) (4OHBP) were the major metabolites produced in hepatocytes from untreated rats. 4-Hydroxybiphenyl-sulfate (4OHBPS) was the major conjugated metabolite. The major conjugate produced by hepatocytes from phenobarbitone and MC pretreated rats was 4-hydroxybiphenyl-glucuronide (19132913) (4OHBPG). Production of 4OHBPS was similar to that seen in untreated rats. Production of free and conjugated 2-hydroxybiphenyl (90437) (2OHBP) and 3-hydroxybiphenyl (580518) was markedly increased by MC, but not by phenobarbitone pretreatment. 2OHBP and 3OHBP reached maximum concentrations after 10min of incubation. Their concentrations decreased to low values by 45min, at which time the concentration of conjugated metabolites had increased. To investigate this lag, rat hepatocytes were preincubated with 0.7microM 4-methylumbelliferone for 60min, then incubated with 70microM biphenyl. The rate of formation of 4OHBPG was significantly increased, whereas the rate of formation of 4OHBPS was relatively unaffected. Hepatocytes were incubated with 7 to 70microM 4OHBP or 7 to 140microM 2OHBP and the effects on 4OHBP or 2OHBP glucuronidation and sulfation were investigated. Sulfate formation was the major conjugating pathway at low 4OHBP or 2OHBP concentrations; however, at high substrate concentrations glucuronidation became the major pathway. The authors suggest that there may be close association of the sulfation enzymes with the surface of the endoplasmic reticulum of hepatocytes. 

DCN-156488; Biotransformation; Aromatic hydrocarbons; In vitro studies; Mammalian cells; Liver cells; Metabolic study; Chemical analysis; Chemical kinetics; Chemical structure; Laboratory animals