Skin cytochrome P450 status and percutaneous penetration: enhanced dermal absorption and altered local disposition of 3,3',4,4'-tetrachlorobiphenyl and pentachlorophenol.
Perspectives in Percutaneous Penetration. Brain KR, Walters KA, eds., Cardiff, UK: STS Publishing, 2000 Jan; 7a:115
Chemical mixture and sequential chemical dermal exposure reflects the real-world scenario in the workplace, environment, or residential setting. Cutaneous metabolism has a great effect on the local and systemic health hazard of a topically applied chemical by modifying its disposition fate and biological activity. To quantify the effects of skin cytochrome (Cyt) P450 induction on local distribution and dermal absorption, 14C labeled 3,3',4,4' -tetrachlorobiphenyl (TCB, in acetone) or pentachlorophenol (PCP, in ethanol) was topically applied to in vivo (n=3), ex vivo (isolated perfused skin, n=4), and in vitro (flow-through diffusion cells, n=7) porcine models, at 40 ug/cm2 with or without Cyt P450 inducer benzo[a]pyrene (B[a]P) pretreatment. Skin Cyt P450 induction enhanced the dermal absorption of TCB and PCP in all the three models. A 2-4 fold increase in 8 h 14C percutaneous absorption was observed in the ex vivo model (TCB 0.11 to 0.46%; PCP 1.1 to 3.2%) and in vitro (TCB 0.21 to 0.48%; PCP 0.20 to 0.66%) due to cutaneous P450 induction. Under P450 induction (control), 5% (2%) and 6% (3%) of the TCB and PCP doses were excreted in urine, respectively. The corresponding values in feces were 4% (3%) and 8% (6%). If the in vivo observation period was prolonged to several weeks, the total absorption was 23-30% for TCB and 50-70% for PCP regardless of skin Cyt P450 induction, indicating the observation duration has to be considered when designing a study to detect the effect of skin P450 on dermal absorption, perhaps as short as 3-5 days. Skin Cyt P450 induction also changed label penetration depth and distribution pattern in local cutaneous tissues, suggesting that the enhanced cutaneous TCB and PCP metabolism can change the toxicity profile (cutaneous vs systemic). On average, 82% and 83% of the topical TCB and PCP doses were recovered. In conclusion, the effects of cutaneous metabolism manipulation by pre-exposed or co-administered enzyme inducer(s) such as B[a]P need to be taken into account in dermal risk assessment and transdermal drug delivery.