Consequences of overexpression of growth hormone in transgenic mice on liver cytochrome P450 enzymes

Abstract

The effect of growth hormone (GH) on cytochrome P450 (CYP) and P450-dependent monooxygenases was studied in 4-, 6-, 8-, and 10-month-old female bovine growth hormone (bGH) transgenic mice that overexpress GH. Nontransgenic female mice (C57/SJL) littermates were used for baseline determinations. The body weights of the bGH mice were approximately 35% greater than those of the controls. The liver weights were 2-fold higher than those of the controls, resulting in a 25-60% increase in liver/body weight ratio during the life span of the bGH mice when compared with the controls. Similar increases in heart and kidney weights were observed. Since the GH transgene was transcriptionally regulated by a metallothionein-I gene promoter, metallothionein concentrations in livers of transgenic and nontransgenic mice were measured. No significant differences were observed. In marked contrast to increases in liver weights, hepatic cytochrome P450 content, benzphetamine N-demethylase, and benzo [a] pyrene hydroxylase activities were decreased by 36, 42 and 75%, respectively. No age-related changes in the decrease of the monooxygenases were observed. Microsomal heme oxygenase (HO) in the liver was induced 44% above the control values. Immunoblot analysis also showed a marked increase in HO-1 in the bGH mice. These results indicate that GH suppresses the carcinogen-metabolizing enzyme benzo [a] pyrene hydroxylase and the drug-metabolizing enzyme benzphetamine N-demethylase. This suppression was accompanied by an induction of HO activity in bGH transgenic mice. The consequences of prolonged exposure to supraphysiological levels of this hormone cannot always be predicted from the known physiological actions of GH.